U.S. patent application number 11/623225 was filed with the patent office on 2007-06-14 for bicyclic indolyl derivatives and methods for their use as serotonergic agents.
This patent application is currently assigned to Wyeth. Invention is credited to Byron Abel Bravo, Wayne Everett Childers, Boyd Lynn Harrison, Micahel Gerard Kelly, Lee E. Schechter, Gan Zhang.
Application Number | 20070135445 11/623225 |
Document ID | / |
Family ID | 33555467 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135445 |
Kind Code |
A1 |
Kelly; Micahel Gerard ; et
al. |
June 14, 2007 |
Bicyclic Indolyl Derivatives and Methods for Their Use as
Serotonergic Agents
Abstract
Bicyclic indolyl derivatives and compositions containing such
compounds are disclosed. Methods of using the bicyclic indolyl
derivatives and compositions containing such composition as
serotonergic agents, such as in the treatment of depression and
anxiety, are also disclosed. In addition, processes for the
preparation of bicyclic indolyl derivatives are disclosed.
Inventors: |
Kelly; Micahel Gerard;
(Thousand Oaks, CA) ; Childers; Wayne Everett;
(New Hope, PA) ; Harrison; Boyd Lynn; (Princeton
Junction, NJ) ; Zhang; Gan; (Niwot, CO) ;
Bravo; Byron Abel; (Eagleville, PA) ; Schechter; Lee
E.; (Toms River, NJ) |
Correspondence
Address: |
WOODCOCK WASHBURN LLP
CIRA CENTRE, 12TH FLOOR
2929 ARCH STREET
PHILADELPHIA
PA
19104-2891
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
33555467 |
Appl. No.: |
11/623225 |
Filed: |
January 15, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10864698 |
Jun 9, 2004 |
7179813 |
|
|
11623225 |
Jan 15, 2007 |
|
|
|
60477575 |
Jun 11, 2003 |
|
|
|
Current U.S.
Class: |
514/253.09 ;
544/364 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 25/00 20180101; A61P 25/30 20180101; C07D 401/12 20130101;
A61P 35/00 20180101; A61P 25/28 20180101; A61P 25/24 20180101; A61P
43/00 20180101 |
Class at
Publication: |
514/253.09 ;
544/364 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 403/14 20060101 C07D403/14 |
Claims
1. (canceled)
2. A method according to claim 8, 9, or 21 wherein: R.sub.2 is H or
methyl.
3. A method according to claim 8, 9, or 21, wherein: R.sub.1 is H
or alkyl; and n is 1.
4. A method according to claim 8, 9, or 21, wherein said compound
is selected from the group consisting of:
(S)-N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-ylbicy-
clo[2.2.2]octane-2-carboxamide;
(R)-N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-ylbicy-
clo[2.2.2]octane-2-carboxamide;
N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-7-methyl-N-pyridin-2-y-
l-bicyclo[2.2.1]heptane-7-carboxamide;
N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-7-methyl-N-pyridin-2-y-
l-bicyclo[2.2.1]heptane-7-carboxamide; and prodrugs, N-oxides and
pharmaceutically-acceptable salts thereof.
5. A method according to claim 8, 9, or 21, wherein said compound
is selected from the group consisting of:
(S)-N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-ylbicy-
clo[2.2.2]octane-2-carboxamide;
(R)-N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-ylbicy-
clo[2.2.2]octane-2-carboxamide; and prodrugs, N-oxides and
pharmaceutically-acceptable salts thereof.
6. (canceled)
7. (canceled)
8. A method of binding 5-HT.sub.1A receptors in a patient in need
thereof, comprising the step of administering to the patient an
effective amount of the compound of formula (I): ##STR10## or a
prodrug, stereoisomer, N-oxide or pharmaceuticallv-acceptable salt
thereof; wherein: R.sub.1 is H, halo or alkyl; R.sub.2 is H or
lower alkyl; and n is 0 or 1.
9. A method of antagonizing 5-HT.sub.1A receptors in a patient in
need thereof, comprising the step of administering to the patient
an effective amount of the compound of formula (I): ##STR11## or a
prodrug, stereoisomer, N-oxide or pharmaceutically-acceptable salt
thereof; wherein: R.sub.1 is H, halo or alkyl; R.sub.2 is H or
lower alkyl; and n is 0 or 1.
10-20. (canceled)
21. A method for treating prostate cancer in a patient in need
thereof, comprising the step of: administering to the patient an
effective amount of the compound of formula (I): ##STR12## or a
prodrug, stereoisomer, N-oxide or pharmaceutically-acceptable salt
thereof; wherein: R.sub.1 is H, halo or alkyl; R.sub.2 is H or
lower alkyl; and n is 0 or 1.
22. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Application Ser.
No. 60/477,575, filed Jun. 11, 2003, the entire disclosure of which
is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to novel piperazine derivatives,
pharmaceutical compositions containing them and methods for their
use. More specifically, the invention relates to novel bicyclic
indolyl derivatives that are serotonergic agents.
BACKGROUND OF THE INVENTION
[0003] Much information concerning the serotonin 5-HT.sub.1A
receptor subtype has been generated since its discovery in 1981
(Pedigo et al., J. Neurochem. 1981, 36, 220) and subsequent cloning
in 1988 (Fargin et al., Nature 1988, 335, 358). Numerous
preclinical studies suggest the potential usefulness of 5-HT.sub.1A
antagonists in the treatment of various diseases and disorders of
the central nervous system (CNS), particularly anxiety and
depression. Preclinical and clinical data now indicate that
compounds that antagonize 5-HT.sub.1A receptors may find use in the
treatment, prevention and amelioration of central nervous system
diseases and disorders, including anxiety, depression,
schizophrenia and cognitive deficits resulting from
neurodegenerative disorders like Alzheimer's disease; the
enhancement of antidepressant activity; the treatment and
amelioration of prostate cancer; and the treatment for smoking
cessation and nicotine withdrawal. K. Rasmussen and V. P. Rocco,
"Recent Progress in Serotonin (5-HT).sub.1A Receptor Modulators,"
Annual Reports in Medicinal Chemistry, Volume 30, J. A. Bristol,
ed., 1-9 (1995); L. E. Schechter and M. G. Kelly, "An Overview of
5-HT.sub.1A Receptor Antagonists: Historical Perspective and
Therapeutic Targets," Current Drugs Serotonin ID Research Alert
1997, 2, 299-309.
[0004] Because antagonists of 5-HT.sub.1A receptors are expected to
be useful in the treatment, prevention and amelioration of central
nervous system diseases, the enhancement of antidepressant
activity, the treatment and amelioration of prostate cancer, and
the treatment for smoking cessation and nicotine withdrawal, it
would be desirable to develop new compounds that are capable of
binding to 5-HT.sub.1A receptors and antagonizing their activity.
The novel bicyclic indolyl derivatives of this invention are
serotonergic agents that antagonize 5-HT.sub.1A receptors and thus
are expected to be beneficial in these and other important
uses.
SUMMARY OF THE INVENTION
[0005] The present invention provides bicyclic indolyl derivatives
that find use as serotonergic agents.
[0006] In one embodiment, the invention is directed to compounds of
formula (I): ##STR1## [0007] or a prodrug, stereoisomer, N-oxide or
pharmaceutically-acceptable salt thereof; [0008] wherein: [0009]
R.sub.1 is H, halo or alkyl; [0010] R.sub.2 is H or lower alkyl;
and [0011] n is 0 or 1.
[0012] In another embodiment, the invention is directed to
compositions, comprising the compound of formula (I); and one or
more pharmaceutically-acceptable carriers.
[0013] The novel compounds of formula (I) preferably bind with
5-HT.sub.1A and, in certain embodiments, are serotonin 5-HT.sub.1A
antagonists, and as such are useful in treating, preventing or
ameliorating several diseases and disorders associated with the
binding and/or antagonism of 5-HT.sub.1A receptors, including the
treatment, prevention and amelioration of central nervous system
diseases and disorders, including anxiety, depression,
schizophrenia and cognitive deficits resulting from
neurodegenerative disorders like Alzheimer's disease; and the
treatment and amelioration of prostate cancer. They are also useful
as co-administered therapeutic agents to enhance the onset or
potency of the antidepressant action of selective serotonin
reuptake inhibitors (SSRI's) and for smoking cessation and relief
of the symptoms resulting from nicotine withdrawal.
DETAILED DESCRIPTION OF THE INVENTION
[0014] In one aspect, the invention is directed to compounds of
formula (I): ##STR2## [0015] or a prodrug, stereoisomer, N-oxide or
pharmaceutically-acceptable salt thereof; [0016] wherein: [0017]
R.sub.1 is H, halo or alkyl; [0018] R.sub.2 is H or lower alkyl;
and [0019] n is 0 or 1.
[0020] R.sub.1 is preferably H or alkyl, more preferably H or lower
alkyl, most preferably H. R.sub.2 is preferably H or methyl, more
preferably H. The symbol n is preferably 1. In certain preferred
embodiments, R.sub.1 is H or alkyl; R.sub.2 is H or methyl; and n
is 1. Combinations of such preferred meanings may be used.
[0021] Especially preferred examples of the compounds of the
invention are the two diastereomeric isomers of formula (I):
##STR3## [0022]
(S)-N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-ylbicy-
clo[2.2.2]octane-2-carboxamide [Formula (Ia)]; and [0023]
(R)-N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-ylbicy-
clo[2.2.2]octane-2-carboxamide [Formula (Ib)]; or prodrug, N-oxide
or pharmaceutically-acceptable salt thereof. The invention also
includes
N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-7-methyl-N-pyridin-2-y-
l-bicyclo[2.2.1]heptane-7-carboxamide;
N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-7-methyl-N-pyridin-2-y-
l-bicyclo[2.2.1]heptane-7-carboxamide; or a prodrug, N-oxide or
pharmaceutically-acceptable salt thereof.
[0024] The term "alkyl", as used herein, whether used alone or as
part of another group, refers to a substituted or unsubstituted
aliphatic hydrocarbon chain and includes, but is not limited to,
straight and branched chains containing from 1 to 12 carbon atoms,
preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon
atoms, and most preferably one carbon atom, unless explicitly
specified otherwise. For example, methyl, ethyl, propyl, isopropyl,
butyl, i-butyl and t-butyl are encompassed by the term "alkyl."
Specifically included within the definition of "alkyl" are those
aliphatic hydrocarbon chains that are optionally substituted.
Suitable substitutions include halo, with fluoro being particularly
preferred. When the term "lower alkyl" is used herein, it refers to
an alkyl, as defined above, containing 1 to 6 carbon atoms,
preferably 1 to 4 carbons, and more preferably one carbon.
[0025] The carbon number as used in the definitions herein refers
to carbon backbone and carbon branching, but does not include
carbon atoms of the substituents, such as alkoxy substitutions and
the like.
[0026] The term "halo" as used herein, refers to chloro, bromo,
fluoro, or iodo.
[0027] When any variable occurs more than one time in any
constituent or in any formula, its definition in each occurrence is
independent of its definition at every other occurrence.
Combinations of substituents and/or variables are permissible only
if such combinations result in stable compounds.
[0028] The compounds employed in the methods of the present
invention may exist in prodrug form. The term "prodrug," as used
herein, refers to compounds specifically designed to maximize the
amount of active species that reaches the desired site of reaction
which are of themselves typically inactive or minimally active for
the activity desired, but through biotransformation are converted
into biologically active metabolites. Typically, prodrugs are
covalently bonded carriers that release the active parent drug, for
example, as according to formula (I), employed in the methods of
the present invention in vivo when such prodrug is administered to
a mammalian subject.
[0029] The term "stereoisomers," as used herein, refers to
compounds that have identical chemical constitution, but differ as
regards the arrangement of the atoms or groups in space.
[0030] It is understood that compounds according to formula (I) may
include one or more asymmetric carbons, and that formula (I)
encompasses all possible stereoisomers and mixtures thereof, as
well as racemic modifications, particularly those that possess the
activities discussed herein. Compounds employed in the present
methods may be isolated in optically active or racemic forms. Thus,
all chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
Stereoisomers of the compounds of formula (I) can be selectively
synthesized or separated in pure, optically-active form using
conventional procedures known to those skilled in the art of
organic synthesis. For example, mixtures of stereoisomers may be
separated by standard techniques including, but not limited to,
resolution of racemic forms, normal, reverse-phase, and chiral
chromatography, preferential salt formation, recrystallization, and
the like, or by chiral synthesis either from chiral starting
materials or by deliberate synthesis of target chiral centers.
[0031] The term "N-oxide," as used herein, refers to compounds
wherein the basic nitrogen atom of either a heteroaromatic ring or
tertiary amine is oxidized to give a quaternary nitrogen bearing a
positive formal charge and an attached oxygen atom bearing a
negative formal charge.
[0032] The term "pharmaceutically acceptable salt", as used herein,
refers to the acid addition salts derived from organic and
inorganic acids. Such salts include but are not limited to, the
acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cinnamoate, dodecylsulfate, ethanesulfonate, fumarate,
glycerophosphate, glycolate, hemisulfate, hydrochloride,
hydrobromide, hydroiodide, lactate, maleate, malonate, mandelate,
methanesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate,
phosphate, pivalate, propionate, pyruvate, salicylate, succinate,
tartrate, toluenesulfonate and tosylate. Also included are the
salts formed when a basic nitrogen-containing group is quaternized
with such agents as a lower alkyl halide, dialkyl sulfate, long
chain halide such as lauryl bromide, aralkyl halides such as benzyl
and phenethyl bromide.
[0033] "Effective amount" refers to an amount of a compound as
described herein that may be effective to inhibit, prevent, or
treat the symptoms of particular disease or disorder. Such diseases
and disorders include, but are not limited to, those pathological
conditions associated with the administration of 5-HT.sub.1A
antagonists (for example, in connection with the treatment and/or
prevention of depression), wherein the treatment or prevention
comprises, for example, inhibiting the activity thereof by
contacting cells, tissues or receptors with compounds of the
present invention. Thus, for example, the term "effective amount",
when used in connection with 5-HT.sub.1A antagonists, for example,
for the treatment of depression, refers to the treatment and/or
prevention and/or amelioration of the condition.
[0034] "Pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
[0035] "In combination with," refers, in certain embodiments, to
the concurrent administration to a patient of SSRI's and the
compounds of formula (I). When administered in combination, each
component may be administered at the same time or sequentially in
any order at different points in time. Thus, each component may be
administered separately but sufficiently closely in time so as to
provide the desired therapeutic effect.
[0036] "Dosage unit" refers to physically discrete units suited as
unitary dosages for the particular individual to be treated. Each
unit may contain a predetermined quantity of active compound(s)
calculated to produce the desired therapeutic effect(s) in
association with the required pharmaceutical carrier. The
specification for the dosage unit forms of the invention may be
dictated by (a) the unique characteristics of the active
compound(s) and the particular therapeutic effect(s) to be
achieved, and (b) the limitations inherent in the art of
compounding such active compound(s).
[0037] "Patient" refers to animals, including mammals, preferably
humans.
[0038] The terms "administer", "administering" or "administration",
as used herein, refer to either directly administering a compound
or composition to a patient, or administering a prodrug derivative
or analog of the compound to the patient, which will form an
equivalent amount of the active compound or substance within the
patient's body.
[0039] The present invention accordingly provides pharmaceutical
compositions that include the compound of formula (I); and
optionally one or more pharmaceutically-acceptable carriers,
excipients, or diluents. The term "carrier", as used herein, shall
encompass carriers, excipients and diluents. Examples of such
carriers are well known to those skilled in the art and are
prepared in accordance with acceptable pharmaceutical procedures,
such as, for example, those described in Remington's Pharmaceutical
Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing
Company, Easton, Pa. (1985), which is incorporated herein by
reference in its entirety. Pharmaceutical acceptable carriers are
those carriers that are compatible with the other ingredients in
the formulation and are biologically acceptable.
[0040] The compounds of formula (I) can be administered orally or
parenterally, neat, or in combination with conventional
pharmaceutical carriers.
[0041] Representative solid carriers include one or more substance
that can act as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aids, binders,
tablet-disintegrating agents, or encapsulating materials. They are
formulated in conventional manner, for example, in a manner similar
to that use for known antihypertensive agents, diuretics and
.beta.-blocking agents. Oral formulations containing the active
compounds of this invention may comprise any conventionally used
oral forms, including tablets, capsules, buccal forms, troches,
lozenges and oral liquids, suspensions or solutions. In powders,
the carrier is a finely divided solid that is in admixture with the
finely divided active ingredient. In tablets, the active ingredient
is mixed with a carrier having the necessary compression properties
in suitable proportion and compacted in the shape and size desired.
The powders and tablets preferably contain up to 99% of the active
ingredient.
[0042] Capsules may contain mixtures of the active compound(s) with
inert fillers and/or diluents such as the pharmaceutically
acceptable starches (e.g. corn, potato or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses, such as
crystalline and microcrystalline celluloses, flours, gelatins,
gums, etc.
[0043] Useful tablet formulations may be made by conventional
compression, wet granulation or dry granulation methods and utilize
pharmaceutically acceptable diluents, binding agents, lubricants,
disintegrants, surface modifying agents (including surfactants),
suspending or stabilizing agents, including, but not limited to,
magnesium stearate, stearic acid, sodium lauryl sulfate,
microcrystalline cellulose, methyl cellulose, sodium carboxymethyl
cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine,
gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate,
complex silicates, calcium carbonate, glycine, dextrin, sucrose,
sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin,
mannitol, sodium chloride, talc, starches, sugars, low melting
waxes, and ion exchange resins. Preferred surface modifying agents
include nonionic and anionic surface modifying agents.
Representative examples of surface modifying agents include, but
are not limited to, poloxamer 188, benzalkonium chloride, calcium
stearate, cetostearyl alcohol, cetomacrogol emulsifying wax,
sorbitan esters, colloidal silicon dioxide, phosphates, sodium
dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
Oral formulations herein may utilize standard delay or time release
formulations to alter the absorption of the active compound(s). The
oral formulation may also consist of administering the active
ingredient in water or a fruit juice, containing appropriate
solubilizers or emulsifiers as needed.
[0044] Liquid carriers can be used in preparing solutions,
suspensions, emulsions, syrups, and elixirs. The active ingredient
can be dissolved or suspended in a pharmaceutically acceptable oil
or fat. The liquid carrier can obtain other suitable pharmaceutical
additives such as, for example, solubilizers, emulsifiers, buffers,
preservatives, sweeteners, flavoring agents, suspending agents,
thickening agents, colors, viscosity regulators, stabilizers or
osmo-regulators. Suitable examples of liquid carriers for oral and
parenteral administration include water (particularly containing
additives as above, e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric
alcohols and polyhydric alcohols, e.g. glycols) and their
derivatives, and oils (e.g. fractionated coconut oil and arachis
oil). For parenteral administration, the carrier can also be an
oily ester such as ethyl oleate and isopropyl myristate. Sterile
liquid carriers are used in sterile liquid form compositions for
parenteral administration. The liquid carrier for pressurized
compositions can be halogenated hydrocarbon or other
pharmaceutically acceptable propellant.
[0045] Liquid pharmaceutical compositions that are sterile
solutions or suspensions can be administered by, for example,
intramuscular, intraperitoneal, or subcutaneous injection. Sterile
solutions can also be administered intravenously. Compositions for
oral administration may be in either liquid or solid form.
[0046] In order to obtain consistency of administration, it is
preferred that a composition of the invention is in the form of a
unit dose. Suitable unit dose forms include tablets, capsules and
powders in sachets or vials. Such unit dose forms may contain from
0.1 to 100 mg of a compound of the invention and preferably from 2
to 50 mg. Still further preferred unit dosage forms contain 5 to 25
mg of a compound of the present invention. The compounds of the
present invention can be administered orally at a dose range of
about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10
mg/kg. Such compositions may be administered from 1 to 6 times a
day, more usually from 1 to 4 times a day.
[0047] When administered for the treatment, prevention or
amelioration of a particular disease state or disorder, it is
understood that the effective dosage may vary depending upon the
particular compound utilized, the mode of administration, the
condition, and severity thereof, of the condition being treated, as
well as the various physical factors related to the individual
being treated. In therapeutic applications, compounds of formula
(I) are provided to a patient already suffering from a disease in
an amount sufficient to cure or at least partially ameliorate the
symptoms of the disease and its complications. An amount adequate
to accomplish this is defined as an "effective amount." The dosage
to be used in the treatment of a specific case must be subjectively
determined by the attending physician. The variables involved
include the specific condition and the weight, age, and response
pattern of the patient. Effective administration of the compounds
of this invention may be given at an oral dose of from about 0.1
mg/day to about 1,000 mg/day. Preferably, administration will be
from about 10 mg/day to about 600 mg/day, more preferably from
about 50 mg/day to about 600 mg/day, in a single dose or in two or
more divided doses. The projected daily dosages are expected to
vary with route of administration.
[0048] Such doses may be administered in any manner useful in
directing the active compounds herein to the patient's bloodstream,
including orally, via implants, parentally (including intravenous,
intraperitoneal, intraarticularly and subcutaneous injections),
rectally, intranasally, topically, ocularly (via eye drops),
vaginally, and transdermally.
[0049] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol. For
administration by intranasal or intrabronchial inhalation, the
compounds of formula (I) can be formulated into an aqueous or
partially aqueous solution.
[0050] The compounds of this invention may also be administered
parenterally or intraperitoneally. Solutions or suspensions of
these active compounds as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a
surfactant such as hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in oils. Under ordinary conditions of storage and use,
these preparations contain a preservative to inhibit the growth of
microorganisms.
[0051] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0052] The compounds of formula (I) can also be administered
transdermally through the use of a transdermal patch. For the
purposes of this disclosure, transdermal administrations are
understood to include all administrations across the surface of the
body and the inner linings of bodily passages including epithelial
and mucosal tissues. Such administrations may be carried out using
the present compounds, or pharmaceutically acceptable salts
thereof, in lotions, creams, foams, patches, suspensions,
solutions, and suppositories (rectal and vaginal).
[0053] Transdermal administration may be accomplished through the
use of a transdermal patch containing the active compound and a
carrier that is inert to the active compound, is non-toxic to the
skin, and allows delivery of the agent for systemic absorption into
the blood stream via the skin. The carrier may take any number of
forms such as creams and ointments, pastes, gels, and occlusive
devices. The creams and ointments may be viscous liquid or
semisolid emulsions of either the oil-in-water or water-in-oil
type. Pastes comprised of absorptive powders dispersed in petroleum
or hydrophilic petroleum containing the active ingredient may also
be suitable. A variety of occlusive devices may be used to release
the active ingredient into the blood stream such as a
semi-permeable membrane covering a reservoir containing the active
ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the
literature.
[0054] The compounds of formula (I) may be administered rectally or
vaginally in the form of a conventional suppository. Suppository
formulations may be made from traditional materials, including
cocoa butter, with or without the addition of waxes to alter the
suppository's melting point, and glycerin. Water soluble
suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0055] Since prodrugs are known to enhance numerous desirable
qualities of pharmaceuticals (e.g., solubility, bioavailability,
manufacturing, etc.) the compounds employed in the present methods
may, if desired, be delivered in prodrug form. Thus, the present
invention contemplates methods of delivering prodrugs. Prodrugs of
the compounds employed in the present invention, for example
formula (I), may be prepared by modifying functional groups present
in the compound in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the parent
compound.
[0056] Accordingly, prodrugs include, for example, compounds
described herein in which a hydroxy, amino, or carboxy group is
bonded to any group that, when the prodrug is administered to a
mammalian subject, cleaves to form a free hydroxyl, free amino, or
carboxylic acid, respectively. Examples include, but are not
limited to, acetate, formate and benzoate derivatives of alcohol
and amine functional groups; and alkyl, carbocyclic, aryl, and
alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and
phenethyl esters, and the like.
[0057] Various forms of prodrugs are known in the art such as those
discussed in, for example, Bundgaard (ed.), Design of Prodrugs,
Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology,
Volume 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.),
Design and Application of Prodrugs, Textbook of Drug Design and
Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal
of Drug Delivery Reviews 1992, 8, 1-38; Bundgaard, Journal of
Pharmaceutical Sciences 1988, 77, 285 et seq.; Higuchi and Stella
(eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical
Society (1975), each of which is incorporated by reference in its
entirety.
[0058] The compounds employed in the methods of the present
invention may be prepared in a number of ways well known to those
skilled in the art. The compounds can be synthesized, for example,
by the methods described below, or variations thereon as
appreciated by the skilled artisan. All processes disclosed in
association with the present invention are contemplated to be
practiced on any scale, including milligram, gram, multigram,
kilogram, multikilogram or commercial industrial scale.
[0059] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Preferred protecting groups
include the benzyloxycarbonyl group and the tert-butyloxycarbonyl
group. Other preferred protecting groups that may be employed in
accordance with the present invention may be described in Greene,
T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis
2d. Ed., Wiley & Sons, 1991.
[0060] This invention also provides methods of utilizing the
compounds of this invention, or a pharmaceutically acceptable salt
thereof, in preventing, treating or ameliorating anxiety,
generalized anxiety disorder, depression, schizophrenia, cognitive
deficits resulting from neurodegenerative diseases like Alzheimer's
Disease, and in the treatment of prostate cancer. The compounds of
this invention can also be used in the treatment, enhancement, or
facilitation of smoking cessation or in comparable methods of
assisting in withdrawal of nicotine-related habits. Each of these
methods comprises administering to a mammal in need thereof,
preferably a human in need thereof, of a pharmaceutically effective
amount of a compound of this invention, or a pharmaceutically
acceptable salt thereof.
[0061] This invention also provides for the use of the compounds of
the invention for the manufacture of a medicament for treating a
central nervous system (CNS) disorder, for treating prostate cancer
or for treating withdrawal symptoms induced by cessation of smoking
or use of nicotine-containing products.
[0062] This invention also provides methods for enhancing the
efficacy of selective serotonin reuptake inhibitors (SSRIs) in a
mammal, the methods comprising co-administering to a mammal in need
thereof pharmaceutically effective amounts of the SSRI in question
and a compound of formula (I). Among the SSRIs that may be
administered in these regimens are fluoxetine hydrochloride,
venlafaxine hydrochloride, paroxetine hydrochloride, nefazodone
hydrochloride, and sertraline hydrochloride. It will be understood
that the SSRIs in these regimens may be administered in dosages and
regimens known in the art for these compounds. These methods may
also be characterized as methods of treatment of maladies such as
depression, anxiety and generalized anxiety disorder in a mammal in
need thereof, the methods comprising co-administering to the mammal
in need thereof of pharmaceutically effective amounts of a compound
of this invention, or a pharmaceutically acceptable salt thereof,
and an SSRI.
Anxiety
[0063] While no clinical trial results have been published,
5-HT.sub.1A antagonists have demonstrated anxiolytic activity in
several animal models, most notably the elevated plus-maze (D. J.
Bill and A. Fletcher, Br. J Pharmacol. 1994, 111, 151P; J-L.
Moreau, et al., Brain Res. Bull. 1992, 29, 901) and the light/dark
box (R. J. Rodgers and J. C. Cole, Eur. J. Pharmacol. 1994, 261,
321). Therefore, 5-HT.sub.1A antagonists may find use as anxiolytic
agents.
Depression
[0064] The 5-HT.sub.1A receptor appears to play a major role in
mediating antidepressant response (J. F. Deakin, et al., Trends
Pharmacol. Sci., 1993, 14, 263). The delay in onset of
antidepressant activity seen with serotonin-specific release
inhibitors (SSRI's) is a result of the activation of
somatodendritic 5-HT.sub.1A autoreceptors and a resulting decrease
in serotonin release (S. Hjorth and S. B. Auerbach, Behav. Brain
Res. 1996, 73, 281). Several clinical studies that combined the
.sup.5-HT.sub.1A antagonist pindolol with several selective
serotonin reuptake inhibitors (SSRI's, e.g., paroxetine) indicate
that addition of the 5-HT.sub.1A antagonist hastens the onset of
action of the SSRI and may even enhance the potency of the SSRI
(Schechter et al., Current Opinion in CPNS Investigational Drugs
1999, 1, 432). Chronic administration of the SSRI leads to an
eventual desensitization of the 5-HT.sub.1A autoreceptor, an
increase in neuronal firing and serotonin release and concomitant
antidepressant activity.
Schizophrenia
[0065] Evidence has accumulated over the last decade to suggest
that serotonin and various serotonin receptors play a role in the
pathophysiology and pharmacological treatment of schizophrenia.
Both receptor binding studies (T. Hashimoto, et al., Life Sci.,
1991, 48, 355) and autoradiography (J. N. Joyce, et al,
Neuropsychopharmacol. 1993, 8, 315; P. W. J. Bumet, et al,
Neuropsychopharmacol., 1996, 15, 442) on postmortem brains of
schizophrenia patients indicate that there is an increase in
5-HT.sub.1A receptor density. While the most efficacious
antipsychotic treatments to date have targeted dopaminergic
neurotransmission, it is clear from binding results that atypical
antipsychotics also possess significant serotonergic affinity (H.
Y. Meltzer, Clin. Neurosci. 1995, 3, 64). Notably, the 5-HT.sub.1A
receptor has been associated with changes in dopaminergic
neurotransmission (M. Hamon, et al., J. Pharmacol. Exp. Ther. 1988,
246, 745; L. E. Schechter, et al., J. Pharmacol. Exp. Ther. 1990,
255, 1335). Furthermore, dysfunctional glutamatergic pathways
appear to be involved in psychotic pathology and decreased
glutamate levels have been demonstrated in schizophrenic brains (K.
Q. Do, et al, J. Neurochem. 1995, 65, 2652; G. C. Tsai, et al.,
Arch. Gen. Psychiatry 1995, 52, 829). Thus, by enhancing glutamate
availability and transmission, 5-HT.sub.1A antagonists may function
as antipsychotic agents.
Cognitive Deficits from Neurodegenerative Disorders
[0066] Alzheimer's disease is characterized by a loss in both
cholinergic and glutamatergic excitatory neurotransmission.
Numerous preclinical studies suggest that blockade of 5-HT.sub.1A
receptors may compensate for the loss in glutamatergic excitatory
input seen in Alzheimer's Disease by enhancing glutamate release
(see Schechter et al., Current Pharmaceutical Design 2002, 8, 139),
and references cited therein). Furthermore, 5-HT.sub.1A antagonists
may compensate for Alzheimer-related cholinergic deficits by
enhancing glutamatergic transduction through the same pathway.
Recently, it has been demonstrated that 5-HT.sub.1A antagonists can
reverse cholinergic- and glutamatergic-associated cognitive
deficits in animal models, including fomix lesion (Harder et al.,
Psychopharmacol. 1996, 127, 245), scopolamine-induced deficits
(Carli et al, Eur. J. Pharmacol. 1995, 283, 133) and MK-801-induced
deficits (Harder et al., Neuropharmacology, 2002, 39, 547). Thus,
5-HT.sub.1A antagonists may provide relief of the cognitive
deficits seen in Alzheimer's disease.
[0067] Studies on the cholinergic deficits observed in Alzheimer's
disease have made it apparent that not all patients can be
characterized by deficits in this system alone (P. T. Francis, et
al., Neurotransmitters and Neuropeptides in Alzheimer's Disease, R.
D. Terry, ed., Raven Press, Ltd., New York, 247-261 (1994)). More
recent studies reveal that glutamatergic function is also severely
disrupted. Glutamate is an important neurotransmitter that can
enhance cognition and physiological phenomena such as long-term
potentiation (LTP), which appears to play a role in mediating
learning and memory processes. The activation of glutamatergic
neurotransmission facilitates memory (U. Stabil, et al., PNAS (USA)
1994, 91, 777), while glutamate antagonists impair learning and
memory as well as LTP in rats (R. G. Morris, et al, Nature 1986,
319, 774; T. V. Bliss and G. L. Collinridge, Nature 1993, 361,
31).
[0068] Studies on the post-mortem brains of Alzheimer's patients
have demonstrated reductions in glutamate receptors in both
neocortex and hippocampus (J. T. Greenmyre, Arch. Neurol. 1986, 43,
1058; W. F. Marangos, et al, Trends Neurosci. 1987, 10, 37). Rich
in glutamatergic neurons, the pyramidal cell layer of the
entorhinal cortex is one of the first areas in the Alzheimer's
brain to develop the morphological hallmarks of Alzheimer's
disease, plaques and tangles. Furthermore, there are reduced levels
of glutamate in the perforant pathway that projects from the
entorhinal cortex to the dentate gyrus (B. T. Hyman, et al., Ann.
Neurol. 1987, 22, 37) and a loss of glutamate staining in the
perforant path terminal zone that has been associated with
Alzheimer's Disease (N. W. Kowal and M. F. Beal, Ann. Neurol. 1991,
29, 162). Thus, there is compelling evidence that a deficit in
glutamatergic neurotransmission is associated with cognitive
impairment and is a pathological finding in Alzheimer's
Disease.
[0069] Data indicate that 5-HT.sub.1A antagonists have a
facilitatory effect on glutamatergic neurotransmission (D. M.
Bowen, et al., Trends Neurosci. 1994, 17, 149). Serotonin
5-HT.sub.1A antagonists have been shown to both potentiate
NMDA-induced glutamate release from pyramidal neurons and
significantly elevate glutamate release when administered alone (S.
N. Dilk, et al., Br. J Pharmacol. 1995, 115, 1169). They inhibit
the tonic hyperpolarizing effect of serotonin on neurons in both
the cortex and hippocampus, which in turn enhances glutamatergic
neurotransmission and signaling (R. Araneda and R. Andrade,
Neuroscience 1991, 40, 399). Coupled with the observation that a
functionally hyper-responsive serotonin system in Alzheimer's
disease may contribute to the cognitive disturbances (D. M.
McLoughlin, et al., Am. J Psychiatry 1994, 151, 1701), the data
suggest that 5-HT.sub.1A antagonists may improve cognition by
removing the inhibitory effects of endogenous serotonin on
pyramidal neurons and enhancing glutamatergic activation and the
ensuing signal transduction.
[0070] Nevertheless, the cholinergic system clearly plays a role in
cognitive processing, and recent therapies designed to improve
cognition in Alzheimer's patients have been targeted at enhancing
cholinergic neurotransmission, either through inhibition of
acetylcholinesterase or by the use of agonists. Postsynaptic M1
muscarinic acetylcholine receptors are located on pyramidal neurons
along with glutamatergic and 5-HT.sub.1A receptor sites. In this
regard, blockade of 5-HT.sub.1A receptors may compensate for the
loss of cholinergic excitatory input by enhancing glutamatergic
transduction through the same pathway. In fact, muscarinic (M1)
signal transduction may be facilitated by blocking the
hyperpolarizing action of serotonin. In addition, there is evidence
that 5-HT.sub.1A receptor antagonists may decrease the formation of
.beta.-amyloid plaques and tangles via its enhancement of
muscarinic M1 receptor signaling and resulting activation of
protein kinase C (J. D. Baxbaum, et al., PNAS (USA), 1993, 90,
9195).
[0071] Preclinical evidence for treating Alzheimer's disease has
been established using available 5-HT.sub.1A antagonists.
WAY-100635 reversed the cognitive deficits induced by fornix
lesions in marmosets (J. A. Harder, et al., Psychopharmacol 1996,
245). WAY-100135 prevented the impairment of spatial learning
caused by intrahippocampal scopolamine, a muscarinic antagonist (M.
Carli, et al., Eur. J. Pharmacol. 1995, 283, 133). NAN-190 has been
shown to augment LTP (N. Sakai and C. Tanaka, Brain Res. 1993, 613,
326). Taken together with the various in vitro data described above
and in the literature, these studies strongly suggest that
treatment with 5-HT.sub.1A receptor antagonists represent a viable
strategy for restoring the multiple deficits associated with
Alzheimer's disease.
Enhancement of Antidepressant Activity
[0072] Co-administration of a 5-HT.sub.1A antagonist would be
expected to inhibit the SSRI-induced activation of pre-synaptic
autoreceptors and, thus, hasten the onset of antidepressant action
of SSRI's. This hypothesis is supported by results from studies in
animal models using more- or less-specific 5-HT.sub.1A antagonists
in combination with SSRI's (K. Briner and R. C. Dodel, Cur. Pharm.
Des. 1998, 4, 291), and references cited therein). Furthermore,
clinical trials have shown that co-administration of the
5-HT.sub.1A antagonist pindolol significantly reduced the median
time needed to achieve a sustained antidepressant response with the
SSRI's paroxetine (M. B. Tome, et al., Int. Clin. Psy. 1997, 12,
630) and fluoxetine (V. Perez, et al., Lancet 1997, 349, 1594).
Therefore, 5-HT.sub.1A antagonists are expected to enhance the
antidepressant activity of SSRI's by reducing the delay in onset of
action seen with this class of drugs.
Prostate Cancer
[0073] In addition to its role as a neurotransmitter, serotonin can
function as a growth factor. Serotonin is found in most
neuroendocrine cells of the human prostate, where it may play a
role in the progression of prostate carcinoma (P. A. Abrahamsson,
et al., Pathol. Res. Pract. 1986, 181, 675; N. M. Hoosein, et al.,
J. Urol. 1993, 149, 479A). The 5-HT.sub.1A antagonist pindobind has
shown antineoplastic activity when tested against the human
prostate tumor cell lines PC3, DU-145 and LNCaP in vitro and
inhibited the growth of the aggressive PC3 cell line in vivo in
athymic nude mice (M. Abdul, et aL, Anticancer Res. 1994, 14,
1215).
Smoking Cessation
[0074] Cessation from chronic use of nicotine or tobacco in humans
results in withdrawal symptoms, including anxiety, irritability,
difficulty concentrating and restlessness. These withdrawal
symptoms have been shown to play an important role in relapse (J.
R. Hughes and D. Hatsukami, Arch. Gen. Psychiatry 1986, 43, 289).
Preclinical evidence indicates that withdrawal from the chronic
administration of nicotine increases the sensitivity of 5-HT.sub.1A
receptors (K. Rasmussen and J. F. Czachura, Psychopharmacology
1997, 133, 343) and enhances the auditory startle reflex in rats
(D. R. Helton, et al., Psychopharmacology 1993, 113, 205).
Serotonin 5-HT.sub.1A antagonists have been shown to attenuate this
nicotine-withdrawal-enhanced startle response (K. Rasmussen, et
al., Synapse 1997, 27, 145; K. Rasmussen, et al., J. Pharmacol.
Exp. Ther. 2000, 294, 688). Thus, 5-HT.sub.1A antagonists may find
clinical use as a pharmacotherapy for smoking cessation. This
excess serotonin activates somatodendritic autoreceptors,
5-HT.sub.1A receptors, which reduces cell firing activity and, in
turn, causes a decrease in serotonin release in major forebrain
areas. This negative feedback limits the increment of synaptic
serotonin that can be induced by antidepressants acutely.
[0075] Recent studies also provide evidence that the anxiogenic
effects induced by withdrawal of nicotine are partially or
primarily mediated by 5-HT.sub.1A receptors in various parts of the
brain, including dorsal hippocampus (Kenny et al.,
Neuropharmacology 2000, 39, 300), dorsal raphe nucleus (Cheeta,
Psychopharmacology 2001, 155, 78) and lateral septum (File et al.,
Eur. J. Pharmacol. 2000, 393, 231). In animal models, anxiogenic
behaviors induced by nicotine withdrawal can be blocked by
treatment with 5-HT.sub.1A antagonists, including NAN-190,
LY206130, WAY-100635 (Rasmussen et al., Synapse 1997, 27, 45) and
LY 426965 (Rasmussen et al., J. Pharmacol. Exp. Ther. 2000, 294,
88). Thus, 5-HT.sub.1A antagonists may find use in the treatment of
the withdrawal symptoms induced by cessation of smoking and the use
of other nicotine-containing products.
[0076] This invention also provides pharmaceutical compositions
utilizing the compounds of this invention. Each composition
comprises an effective amount of a compound of this invention and
one or more pharmaceutically acceptable carriers or excipients.
[0077] The variables involved in determining a desirable dose for
an individual recipient include the specific disease or disorder
and the size, age and response pattern of the patient. The novel
method of the invention for treating conditions related to or are
affected by the 5-HT.sub.1A receptor comprise administering to
warm-blooded animals, including humans, an effective amount of at
least one compound of this invention or its pharmaceutically
acceptable salt form. The compounds may be administered orally,
rectally, parenterally or topically to the skin and mucosa. A daily
human dose may be administered from about 0.01-1000 mg/kg for oral
application, preferably 0.5-500 mg/kg, and 0.1-100 mg/kg for
parenteral application, preferably 0.5-50 mg/kg.
[0078] Applicable solid carriers can include one or more substances
which may also act as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aids, binders or
tablet-disintegrating agents or encapsulating materials. In
powders, the carrier is a finely divided solid which is in
admixture with the finely divided active ingredient. In tablets,
the active ingredient is mixed with a carrier having the necessary
compression properties in suitable proportions and compacted in the
shape and size desired. The powders and tablets preferably contain
up to 99% of the active ingredient. Suitable solid carriers
include, for example, calcium phosphate, magnesium stearate, talc,
sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,
low melting waxes and ion exchange resins.
[0079] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups and elixirs. The active ingredient
in this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g. cellulose
derivatives, preferable sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
[0080] Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by, for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. Oral
administration may be either liquid or solid composition form.
[0081] The compounds of formula (I) can be prepared by known
methods from known starting materials that are available by
conventional methods. Such methods include acylating an amine of
formula (II) (where R.sub.1 is as defined above) with bicyclic
carboxylic acids of general formula (III) (where R.sub.2 is defined
above) or an acylating derivative thereof. Examples of acylating
derivatives include the acid halides (e.g., acid chloride),
anhydrides, imidazolides (e.g., obtained form carbonyldiimidazole)
and activated esters. ##STR4## The starting materials of formula
(II) may be prepared by the general route disclosed in
EP-B1-0,512,755 and specifically by the exemplified route described
in WO 95/33743, the disclosures of which are incorporated herein by
reference.
[0082] Reaction of cyclohexadiene with an acrylate ester derivative
using literature methods (Tichy et al., Coll. Czech. Chem. Commun.
1970, 35, 459; Boehme et al., J. Am. Chem. Soc. 1958, 80, 5488)
provides bicyclo[2.2.2]cyclooct-5-ene ester derivatives of formula
(IV), which may be reduced (using, for example, 10% palladium on
carbon under a hydrogen atmosphere as in Christol et al., Org.
Magn. Res. 1981, 17, 110) to give saturated bicyclic esters of
formula (V). Hydrolysis (for example, using a base such as sodium
hydroxide in a suitable solvent such as methanol) provides the
required racemic starting material of formula (III) (Scheme 1).
##STR5##
[0083] The individual enantiomers of
bicyclo[2.2.2]octane-2-carboxylic acids may be obtained through
separation of the racemic mixture by methods known to one skilled
in the art of organic synthesis. Alternatively, the enantiomers of
bicyclo[2.2.2]octane-2-carboxylic acid may be obtained via a
synthetic route that utilizes a chiral auxiliary reagent in an
intermolecular Diels-Alder reaction. Such conditions are known and
have been used to prepare bicyclo[2.2.2]oct-5-ene ester
derivatives. For example, compound of formula (VIa) was synthesized
according to Hansen et al.(J. Org. Chem. 1998, 63, 775), and, after
hydrogenation of the double bond (using, for example, 10% palladium
on carbon in an alcoholic solvent), the chiral auxiliary ester
moiety could be removed under the influence of a base such as
lithium hydroxide to provide the (S)-enantiomer of
bicyclo[2.2.2]octane-2-carboxylic acid of formula(IIIa), as shown
in Scheme 2. ##STR6##
[0084] The opposite (R)-enantiomer of
bicyclo[2.2.2]octane-2-carboxylic acid can be prepared as shown in
Scheme 3, by utilizing the opposite enantiomer of the chiral
auxiliary reagent, and the methodology reported by Hansen et al.
(J. Org. Chem. 1998, 63, 775). Thus treatment of the ester (VIb),
using the conditions shown in Scheme 2, provided the ester (VIIb),
which provided, upon hydrolysis, the (R)-enantiomer of
bicyclo[2.2.2]octane-2-carboxylic acid (IIIb). ##STR7##
[0085] The required bicyclo[2.2.1]heptane-7-carboxylic acid of
formula (VIII) can be prepared as shown in Scheme 4, using the
procedure described by Stapersma and Klump (Tetrahedron 1981, 37,
187), wherein 7-bromobicyclo[2.2.1]heptane is treated with lithium
di-t-butylbiphenylide (Freeman and Hutchinson, Tet. Lett. 1976,
1849), followed by carbon dioxide. ##STR8##
[0086] The 7-substituted bicyclo[2.2.1]heptane-7-carboxylic acid
intermediates of formula (XII) can be prepared according to
literature procedures, for example, as outlined in Scheme 5. A
Diels-Alder reaction between cyclopentadiene and an appropriate
acrylic acid affords exo-2-alkyl bicyclo[2.2.1]heptene-2-carboxylic
acids of formula (IX). An acid-catalyzed rearrangement provides
lactones of formula (X), which can be hydrolyzed in situ and
oxidized to the desired 7-substituted
bicyclo[2.2.1]heptan-2-one-7-carboxylic acids of formula (XI) with
ruthenium tetroxide (generated in situ from ruthenium chloride and
sodium periodate). A Wolff-Kishner reduction yields the final
product (XII). ##STR9##
[0087] The present invention will now be illustrated by reference
to the following specific, non-limiting examples. Those skilled in
the art of organic synthesis may be aware of still other synthetic
routes to the invention compounds. The reagents and intermediates
used herein are either commercially available or prepared according
to standard literature procedures.
EXAMPLES
Intermediate 1
Bicyclo[2.2.2]octane-2-Carboxylic Acid
[0088] Sodium hydroxide (2.5N, 22.4 mL, 56 mmol) was added to a
methanolic solution of methyl bicyclo[2.2.2]octane-2-carboxylate
(4.7 g, 28 mmol in 50 mL) at ambient temperature and the mixture
was stirred for 16 hours. The solvent was concentrated in vacuo,
water added (20 mL) and the solution made acidic with 1N aqueous
HCl. The product was extracted into dichloromethane (3.times.50
mL), the combined organic layers washed with water (25 mL), dried
over anhydrous magnesium sulfate, filtered and concentrated on a
rotary evaporator to afford the titled compound of formula (III) as
a white solid (4.3 g, 100% yield).
[0089] MS (ESI) m/z=: 155 (M+H).sup.+. Elemental Analysis for:
C.sub.9H.sub.14O.sub.2 Calculated: C, 70.10; H, 9.15 Found: C,
70.53; H, 9.25
Intermediate 2
(3R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl-(2S)-bicyclo[2.2.2]oct-5-ene-2-
-carboxylate
[0090] Compound (VIa) was synthesized according to Hansen et al.
(J. Org. Chem. 1998, 63, 775) in two steps starting from
(R)-(-)-pantolactone (11.5 g, 88.4 mmol) and acroloyl chloride
(10.14 g, 112 mmol). It was obtained as a light yellow powder by
recrystallization from diethyl ether/hexane.
[0091] MS (+ESI) m/z=265 (M+H).sup.+. Elemental Analysis for:
C.sub.15H.sub.20O.sub.4 Calculated: C, 68.16; H, 7.63 Found: C,
67.87; H, 7.68.
Intermediate 3
(3R)-4,4-Dimethyl-2-oxotetrahydrofuran-3-yl-(2S)-bicyclo[2.2.2]octane-2-ca-
rboxylate
[0092] To the solution of compound (VIa) (Intermediate 2, 20 g,
75.8 mmol) in methanol (100 mL) was added a catalytic amount of 10%
palladium on carbon (1 g) and the mixture was hydrogenated in a
Parr shaker at 40 psi. After three hours, the mixture was filtered
through a bed of celite, the catalyst was washed with methanol and
the solution concentrated and dried under vacuum. The crude product
of formula (VIIa) was obtained as a light brown solid which was
used without any further purification (18.2 g, 90%).
[0093] MS (+ESI) m/z=267 (M+H).sup.+. Elemental Analysis for:
C.sub.15H.sub.22O.sub.4 Calculated: C, 67.64; H, 8.33 Found: C,
67.00; H, 8.52.
Intermediate 4
(S)-Bicyclo[2.2.2]octane-2-carboxylic Acid
[0094] The product of formula (VIIa) (Intermediate 3, 18.0 g, 67.7
mmol) was dissolved in tetrahydrofuran (100 mL) and the resulting
solution cooled to 5-10.degree. C. A solution of lithium hydroxide
(7 g) in water (140 mL) was added slowly, maintaining the reaction
temperature to below 25.degree. C. and the mixture was stirred for
24 hours at room temperature, then concentrated in vacuo until most
of tetrahydrofuran had been removed. Concentrated HCl was added
drop-wise to adjust the pH to 2, water (60 mL) was added and the
slurry stirred at 0-10.degree. C. for one hour. The precipitate was
isolated by filtration, and dried in a vacuum oven. The crude
product of formula (IIIa) was used without any further purification
(9.35 g, 90%).
[0095] MS (-ESI) m/z=153 (M-H).sup.-. Elemental Analysis for:
C.sub.9H.sub.14O.sub.2 Calculated: C, 70.10; H, 9.15 Found: C,
69.50; H, 9.22.
Intermediate 5
(R)-Bicyclo[2.2.2]octane-2-carboxylic Acid
[0096] The (R)-enantiomer of formula (IIIb) was prepared, starting
from (S)-(+)-pantolactone (10 g, 76.9 mmol) and acryloyl chloride
(8.81 g, 97.4 mmol), using the method of Hansen et. al., J. Org.
Chem. 1998, 63, 775) and the synthetic methods described for
Intermediates 3 and 4.
[0097] MS (-ESI) m/z=153 (M-H).sup.-. Elemental Analysis for:
C.sub.9H.sub.14O.sub.2 Calculated: C, 70.10; H, 9.15 Found: C,
69.97; H, 9.10.
Intermediate 6
Bicyclo[2.2.1]heptane-7-carboxylic Acid
[0098] To a solution of 4-4'-di-t-butylbiphenyl (8.25 g, 31 mmol)
in anhydrous tetrahydrofuran (70 mL) under a nitrogen atmosphere
was added freshly cleaned lithium wire (0.21 g, 30 mmol). The
resulting mixture was stirred at room temperature for 15 minutes to
initiate reaction, then cooled in an ice bath and stirred for an
additional 4 hours. The resulting blue solution was cooled with a
dry ice/acetone bath and a solution of
7-bromo-bicyclo[2.2.1]heptane (2.0 g, 11.4 mmol) in anhydrous
tetrahydrofuran (5 mL) was added in one portion. The reaction
mixture was stirred for 20 minutes, during which time the blue
color changed to orange. Solid dry ice was then added to the
reaction, which became colorless. The dry ice bath/acetone bath was
removed and the reaction was stirred for 2 hours, during which time
it came up to room temperature. 2.5 N aqueous sodium hydroxide (200
mL) was added and the mixture was stirred for 5 minutes. The layers
were separated and the aqueous layer was extracted twice with
diethyl ether (50 mL). The aqueous layer was then made acidic by
addition of concentrated HCl and extracted with three portions of
diethyl ether (75 mL). The combined organic layers were dried over
anhydrous magnesium sulfate and concentrated to yield the desired
compound of formula (VIII) as a white solid (1.54 g, 96%),
mp=74-75.degree. C. (lit. mp=77.5-785.degree. C., J. Am. Chem. Soc.
1954, 76, 4072).
[0099] MS 9-ESI) m/z=139 (M-H).sup.-. Elemental Analysis for
C.sub.8H.sub.12O.sub.2 Calculated: C: 68.55; H: 8.63 Found: C:
67.97; H: 8.57.
Intermediate 7
Exo-2-methylbicyclo[2.2.1]hept-5-ene-2-carboxylic Acid
[0100] A mixture of cyclopentadiene (freshly prepared from
dicyclopentadiene, 62.0 g, 0.94 mol) and methacrylic acid (69.8 g,
0.81 mol) was refluxed at 90.degree. C. for four hours. The
resulting mixture was subjected to vacuum distillation under
reduced pressure (2 mm). The fraction boiling between 69.degree. C.
and 110.degree. C. was collected and yielded a white solid upon
standing, which was shown to be a mixture of the endo- and
exo-isomers, with the exo-isomer predominating. The pure
exo-2-methyl-bicyclo[2.2.1]heptene-2-carboxylic acid of formula
(IX) was isolated from the mixture by recrystallizing twice from
petroleum ether (bp 40-60.degree. C.), to give 30.5 g of the
desired product as a white solid, mp=82-83.degree. C. (lit.
mp=82-83.degree. C., J. Org. Chem. 1979, 44, 2206).
[0101] MS (-ESI) m/z=151 (M-H).sup.-. Elemental Analysis for
C.sub.9H.sub.12O.sub.2 Calculated: C: 71.03; H: 7.95 Found: C:
71.37; H: 8.19.
Intermediate 8
3a-Methylhexahydro-3H-1,4-methanocyclopenta[c]furan-3-one
[0102] Exo-2-methyl-bicyclo[2.2.1]heptene-2-carboxylic acid (8.06
g, 53 mmol, Intermediate 7) was treated under ice cooling with 75%
aqueous sulfuric acid (100 mL). The resulting mixture was stirred
overnight, during which time it came up to room temperature. The
reaction was then poored onto a mixture of ice and water (1000 g)
and a white precipitate forms. The resulting mixture was extracted
with three 200 mL portions of diethyl ether. The combined organic
layers were dried over anhydrous magnesium sulfate and concentrated
on a rotary evaporator to yield a white solid (7.73 g). The solid
was recrystallized from ethanol to give the desired product of
formula (X) as white needles (5.9 g, 73%), mp=125-127.degree. C.
(lit. mp=125-126.degree. C., J. Org. Chem. 1979, 44, 2206).
[0103] MS (+ESI) m/z=153 (M+H).sup.+. Elemental Analysis for
C.sub.9H.sub.12O.sub.2 Calculated: C: 71.03; H: 7.95 Found: C:
70.92; H: 8.10.
Intermediate 9
7-Methyl-2-oxobicyclo[2.2.1]heptane-2-carboxylic Acid
[0104] The product from Intermediate 8 (compound of formula (X),
4.9 g, 32.2 mmol) was suspended in 0.5 N aqueous sodium hydroxide
(70 mL, 35 mmol) and stirred at 100.degree. C. for 45 minutes,
during which time a clear solution formed. The resulting solution
was cooled to room temperature and two drops of 1% ethanolic
phenolphthalein solution were added. The solution was then
neutralized with 0.1 N aqueous HCl. To the neutral solution was
added water (35 mL), carbon tetrachloride (33 mL) and acetonitrile
(33 mL). To the stirred reaction mixture was then added ruthenium
(III) chloride hydrate (0.25 g), followed by sodium periodate
(20.67 g, 96.6 mmol). The resulting mixture was then stirred at
room temperature for 24 hours, then water (50 mL) and diethyl ether
(100 mL) were added. Stirring was continued for 5 minutes, then the
layers were separated. The aqueous layer was extracted twice more
with diethyl ether (50 mL). The combined organic layers were dried
over anhydrous magnesium sulfate and concentrated on a rotary
evaporator to yield a purple solid. The solid was dissolved in
diethyl ether (75 mL) and filtered through a bed of celite to
remove the remaining purple impurity. The clear solution was
concentrated on a rotary evaporator to yield the desired product of
formula (XI) as a white solid (3.16 g, 58%), mp=204-206.degree. C.
(lit. mp=206-208.degree. C., Tetrahedron 1972, 28, 4259).
[0105] MS (-ESI) m/z=167 (M-H).sup.-. Elemental Analysis for
C.sub.9H.sub.12O.sub.3 Calculated: C: 64.27; H: 7.19 Found: C:
63.74; H: 7.31.
Intermediate 10
7-Methylbicyclo[2.2.1]heptane-7-carboxylic Acid
[0106] Freshly cleaned sodium metal (5.25 g, 228.3 mmol) was cut
into small pieces and added to dry diethylene glycol (120 mL) under
a nitrogen atmosphere. The resulting mixture was stirred at
80.degree. C. for 15 minutes to complete formation of the sodium
salt. The resulting orange solution was cooled to room temperature
and a solution of Intermediate 9 (compound (XI)), 3.1 g, 18.5 mmol)
in dry diethylene glycol (20 mL) was added, followed to 98.5%
hydrazine (3.65 mL, 114.5 mmol). The resulting mixture was then
refluxed (bath temperature 200.degree. C.) for 50 hours. The dark
orange reaction mixture was cooled to room temperature, poured into
water (400 mL), and made acidic by addition of concentrated HCl.
The resulting white precipitate was collected by vacuum filtration,
washed with water, air-dried and taken up in diethyl ether (400
mL). The ether solution was dried over anhydrous magnesium sulfate,
treated with acidic decolorizing carbon and concentrated on a
rotary evaporator to yield the desired product of formula (XII) as
an off-white solid (2.36 g, 84%), mp=192-195.degree. C. (lit.
mp=194-195.degree. C., J. Org. Chem. 1979, 44, 2206).
[0107] MS (-ESI) m/z=153 (M-H).sup.-. Elemental Analysis for
C.sub.9H.sub.14O.sub.2 Calculated: C: 70.10; H: 9.15 Found: C:
70.23; H: 9.32.
Example 1
(S)-N-{(2R)-2-[4-(1H-Indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-yl-bicy-
clo[2.2.2]octane-2-carboxamide
[0108] A solution of (S)-bicyclo[2.2.2]octane-2-carboxylic acid
(Intermediate 4, 1.0 g, 6.48 mmol) and dimethylformamide (2 drops)
in dichloromethane (5 mL) was treated with the dropwise addition of
2 equivalents of oxalyl chloride (2M in dichloromethane, 6.5 mL) at
0.degree. C. under nitrogen. After stirring for two hours, the
mixture was concentrated on a rotary evaporator to afford the acid
chloride as a light yellow oil. A solution of
(R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl] piperazine
(2.17 g, 6.48 mmol) in dichloromethane (20 mL) was treated at
0.degree. C. with the dropwise addition of a dichloromethane
solution of the freshly prepared
(S)-bicyclo[2.2.2]octane-2-carboxylic acid chloride (6.48 mmol in 5
mL). After stirring for 16 hours the mixture was poured onto hexane
(100 mL) to precipitate the titled compound as the
monohydrochloride salt (1.77 g, 51%), mp=180-182.degree. C.
[0109] MS (+ESI) m/z=472 (M+H).sup.+. [.alpha.] 25/D=+31.24 (c=1,
MeOH) Elemental Analysis for: C.sub.29H.sub.37N.sub.5O.cndot.1
HCl.cndot.1.5 H.sub.2O Calculated: C, 65.09; H, 7.72; N, 13.09
Found: C, 65.23; H, 7.41; N, 13.49.
Example 2
(R)-N-[(2R)-2-[4-(1H-Indol-4-yl)-1-piperazinyl]propyl]-N-2-pyridin-2-yl-bi-
cyclo[2.2.2]octane-2-carboxamide
[0110] A solution of (R)-bicyclo[2.2.2]octane-2-carboxylic acid
(Intermediate 5, 0.80 g, 5.19 mmol) and dimethylformamide (2 drops)
in dichloromethane (5 mL) was treated with the dropwise addition of
2 equivalents of oxalyl chloride (2M in dichloromethane, 5.2 mL) at
0.degree. C. under nitrogen. After stirring for one hour, the
mixture was concentrated on a rotary evaporator to afford the acid
chloride as a light yellow oil. A solution of
(R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl] piperazine
(1.92 g, 5.72 mmol) in dichloromethane (25 mL) was treated at
0.degree. C. with the dropwise addition of a dichloromethane
solution of the freshly prepared
(R)-bicyclo[2.2.2]octane-2-carboxylic acid chloride (5 mL). After
stirring for 16 hours the mixture was poured onto hexane (100 mL)
and a yellow oil formed. The oil was obtained by decanting and was
partitioned between dichloromethane (100 mL) and saturated aqueous
sodium bicarbonate (100 mL). The organic layer was dried over
anhydrous sodium sulfate and concentrated on a rotary evaporator.
The desired product was obtained as the dihydrochloride salt by
treating the residue with excess HCl in ethyl acetate/diethyl ether
to yield a white solid (1.64 g, 56%), mp=186-190.degree. C.
[0111] MS (+) 472 (M+H).sup.+. [.alpha.] 25/D=-25.45 (c=1, MeOH).
Elemental Analysis for: C.sub.29H.sub.37N.sub.5O.cndot.2
HCl.cndot.1 H.sub.2O Calculated: C, 61.91; H, 7.35; N, 12.45 Found:
C, 62.03; H, 7.50; N, 12.31.
Example 3
N-{(2R)-2-[4-(1H-Indol-4-yl)piperazin-1-yl]propyl}-N-pyridin-2-yl-bicyclo[-
2.2.1]heptane-7-carboxamide
[0112] A solution of bicyclo[2.2.1]heptane-7-carboxylic acid
(Intermediate 6, 0.26 g, 1.86 mmol) and dimethylformamide (1 drop)
in dichloromethane (7 mL) was treated with the dropwise addition of
2.2 equivalents of oxalyl chloride (2M in dichloromethane, 2.08 mL)
at 0.degree. C. under nitrogen. After stirring for three hours, the
mixture was concentrated on a rotary evaporator to afford the acid
chloride as a yellow oil. The freshly prepared acid chloride was
dissolved in dry dichloromethane (7 mL), cooled to 0.degree. C. and
treated with a solution of and
(R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl]piperazine
(0.30 g, 0.9 mmol) in dichloromethane (10 mL). The resulting
mixture was stirred for 48 hours, during which time it came up to
room temperature. The reaction mixture was diluted with
dichloromethane (50 mL) and washed with saturated aqueous sodium
bicarbonate. The organic layer was dried over anhydrous sodium
sulfate and concentrated on a rotary evaporator. The desired
product was isolated by chromatography on silica gel using
methanol/dichloromethane and converted to the monohydrochloride
salt by addition of HCl in ethyl acetate/diethyl ether (0.21 g,
46%), mp=176-179.degree. C.
[0113] MS (+ESI) m/z=458 (M+H).sup.+. [.alpha.] 25/D=+35.6 (c=1,
MeOH). Elemental Analysis for: C.sub.28H.sub.35N.sub.5O.cndot.1
HCl.cndot.1 H.sub.2O Calculated: C, 65.67; H, 7.48; N, 13.68 Found:
C, 65.78; H, 7.44; N, 13.46.
Example 4
N-{(2R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]propyl}-7-methyl-N-pyridin-2-yl-
-bicyclo[2.2.1]heptane-7-carboxamide
[0114] A solution of 7-methyl-bicyclo[2.2.2]heptane-7-carboxylic
acid (Intermediate 10, 0.28 g, 1.80 mmol) and dimethylformamide (1
drop) in dichloromethane (5 mL) was treated with the dropwise
addition of 2.2 equivalents of oxalyl chloride (2M in
dichloromethane, 2.0 mL) at 0.degree. C. under nitrogen. The
reaction was stirred overnight, during which time it came up to
room temperature. The mixture was concentrated on a rotary
evaporator to afford the acid chloride as a yellow oil. The freshly
prepared acid chloride was dissolved in dry dichloromethane (10
mL), cooled to 0.degree. C. and treated with a solution of
(R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl] piperazine
(0.30 g, 0.9 mmol) in dichloromethane (7 mL), followed by
triethylamine (0.18 g, 1.8 mmol). The resulting mixture was stirred
for 96 hours, during which time it came up to room temperature. The
reaction mixture was concentrated on a rotary evaporator to remove
excess solvent and triethylamine. The residue was partitioned
between dichloromethane (100 mL) and saturated aqueous sodium
bicarbonate (75 mL). The aqueous layer was extracted with two
additional portions of dichloromethane (30 mL). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated on a rotary evaporator. The desired product was
isolated by chromatography on silica gel using
methanol/dichloromethane and converted to the monohydrochloride
salt by addition of HCl in ethyl acetate/diethyl ether (0.36 g,
76%), mp=236-238.degree. C.
[0115] MS (+ESI) m/z=472 (M+H).sup.+. [.alpha.] 25/D=+37.1 (c=1,
MeOH). Elemental Analysis for: C.sub.29H.sub.37N.sub.5O.cndot.1
HCl.cndot.1 H.sub.2O Calculated: C, 66.20; H, 7.66; N, 13.31 Found:
C, 65.95; H, 7.51; N, 13.26.
Serotonin 5-HT.sub.1A Binding Profile
[0116] Affinity for the serotonin 5-HT.sub.1A receptor was
established by assaying the test compound's ability to displace
[.sup.3H]8-OH-DPAT from its binding site on the receptor complex in
CHO cells stably transfected with the human 5-HT.sub.1A receptor
following the procedure described by Dunlop et al, J. Pharmacol.
Toxicol. Methods 1998, 40, 47. The compounds of this invention
displayed high affinity for the 5-HT.sub.1A receptor, as shown in
Table 1.
In vitro Functional Activity
[0117] The compounds of formula (I) displayed 5-HT.sub.1A
antagonist activity, as measured by the test compound's ability to
antagonize the ability of the 5-HT.sub.1A full agonist 8-OH-DPAT to
inhibit forskolin-stimulated cyclic-AMP turnover in CHO cells
stably transfected with the human 5-HT.sub.1A receptor following
the procedure described by Dunlop et al., J. Pharmacol. Toxicol.
Methods 1998, 40, 47. TABLE-US-00001 TABLE 1 5-HT.sub.1A cAMP
Compound Ki (nM) IC.sub.50(nM) Example 1 0.68 4.1 Example 2 0.69
2.2 Example 3 0.98 74.5 Example 4 0.45 6.7
[0118] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges and
specific embodiments therein are intended to be included.
[0119] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0120] Those skilled in the art will appreciate that numerous
changes and modifications can be made to the preferred embodiments
of the invention and that such changes and modifications can be
made without departing from the spirit of the invention. It is,
therefore, intended that the appended claims cover all such
equivalent variations as fall within the true spirit and scope of
the invention.
* * * * *