U.S. patent application number 13/428090 was filed with the patent office on 2012-08-02 for 4-substituted azaadamantane derivatives and methods of use thereof.
Invention is credited to William H. Bunnelle.
Application Number | 20120196890 13/428090 |
Document ID | / |
Family ID | 39788936 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120196890 |
Kind Code |
A1 |
Bunnelle; William H. |
August 2, 2012 |
4-SUBSTITUTED AZAADAMANTANE DERIVATIVES AND METHODS OF USE
THEREOF
Abstract
The invention relates to compounds that are 4-substituted
azaadamantane derivatives, compositions comprising such compounds,
and methods of using such compounds and compositions.
Inventors: |
Bunnelle; William H.;
(Mundelein, IL) |
Family ID: |
39788936 |
Appl. No.: |
13/428090 |
Filed: |
March 23, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12052061 |
Mar 20, 2008 |
8163915 |
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13428090 |
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60896751 |
Mar 23, 2007 |
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Current U.S.
Class: |
514/294 |
Current CPC
Class: |
A61P 25/18 20180101;
A61P 17/02 20180101; A61P 25/04 20180101; A61P 25/28 20180101; A61P
25/00 20180101; A61P 25/14 20180101; A61P 25/16 20180101; C07D
471/18 20130101; A61P 21/00 20180101; A61P 31/04 20180101; A61P
39/00 20180101; A61P 9/10 20180101; A61P 29/00 20180101; A61P 25/24
20180101; A61P 25/34 20180101; A61P 43/00 20180101; A61P 31/14
20180101; A61P 3/10 20180101 |
Class at
Publication: |
514/294 |
International
Class: |
A61K 31/439 20060101
A61K031/439; A61P 25/18 20060101 A61P025/18; A61P 31/14 20060101
A61P031/14; A61P 25/34 20060101 A61P025/34; A61P 25/00 20060101
A61P025/00; A61P 25/28 20060101 A61P025/28 |
Claims
1.-8. (canceled)
9. A method for treating a disorder selected from the group
consisting of mild cognitive impairment, age-associated memory
impairment (AAMI), senile dementia, AIDS dementia, Pick's Disease,
dementia associated with Lewy bodies, dementia associated with
Down's syndrome, amyotrophic lateral sclerosis, Huntington's
disease, smoking cessation, schizoaffective disorder, bipolar and
manic disorders, diminished CNS function associated with traumatic
brain injury, acute pain, post-surgical pain, chronic pain, and
inflammatory pain, said method comprising the step of administering
to a subject in need thereof the compound of the formula (I), or a
pharmaceutically acceptable salt, amide or prodrug thereof, wherein
the compound of formula I comprises: ##STR00009## wherein Y.sup.1
is a bond, --N(R.sup.X)--C(O)--, --O--,
--N(R.sup.X)--C(O)--N(R.sup.Y)--, --O--C(O)--, or --N(R.sup.Z)--; A
is aryl, heteroaryl, heterocycle, cycloalkyl, cycloalkenyl,
arylalkyl, heteroarylalkyl, heterocyclealkyl, cycloalkylalkyl, or
cycloalkenylalkyl wherein the aryl, heteroaryl, heterocycle,
cycloalkyl, cycloalkenyl, the aryl moiety of arylalkyl, the
heteroaryl moiety of the heteroarylalkyl, the heterocycle moiety of
the heterocyclealkyl, the cycloalkyl moiety of the cycloalkylalkyl,
and the cycloalkenyl moiety of the cycloalkenylalkyl are each
independently unsubstituted or substituted; and R.sup.X, R.sup.Y,
and R.sup.Z, at each occurrence, are each independently hydrogen,
alkyl, or haloalkyl; or a pharmaceutically acceptable salt, amide
or prodrug thereof.
10. A method for treating a disorder selected from the group
consisting of attention deficit disorder, attention deficit
hyperactivity disorder (ADHD), Alzheimer's disease (AD),
Parkinson's disease, Tourette's syndrome, schizophrenia, and
cognitive deficits associated with schizophrenia (CDS), said method
comprising the step of administering to a subject in need thereof
the compound of claim 9, or a pharmaceutically acceptable salt,
amide or prodrug thereof.
11. A method for treating disorder selected from the group
consisting of schizophrenia and cognitive deficits associated with
schizophrenia (CDS), or combination thereof, comprising the step of
administering to a subject in need thereof the compound of claim 9,
or a pharmaceutically acceptable salt, amide or prodrug thereof,
and one or more atypical antipsychotics.
12-13. (canceled)
14. The method of claim 9, wherein the compound is selected from
the group consisting of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-2-naphthyloxime; 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(pentafluorobenzyl)oxime;
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-(4-chlorophenyl)oxime;
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(6-chloropyridin-3-yl)oxime;
N-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylidene-1H-indole-3-carbohydrazide;
and 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-benzyloxime; or a
pharmaceutically acceptable salt, amide or prodrug thereof.
15. The method of claim 10, wherein the compound is selected from
the group consisting of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-2-naphthyloxime; 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(pentafluorobenzyl)oxime;
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-(4-chlorophenyl)oxime;
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(6-chloropyridin-3-yl)oxime;
N-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylidene-1H-indole-3-carbohydrazide;
and 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-benzyloxime; or a
pharmaceutically acceptable salt, amide or prodrug thereof.
16. The method of claim 11, wherein the compound is selected from
the group consisting of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-2-naphthyloxime; 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(pentafluorobenzyl)oxime;
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-(4-chlorophenyl)oxime;
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(6-chloropyridin-3-yl)oxime;
N-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylidene-1H-indole-3-carbohydrazide;
and 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-benzyloxime; or a
pharmaceutically acceptable salt, amide or prodrug thereof.
Description
[0001] This application claims priority from U.S. Provisional
Patent Application Ser. No. 60/896,751 filed Mar. 23, 2007, which
is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] The invention relates to 4-substituted azaadamantane
derivatives, compositions comprising such compounds, and methods of
preventing or treating conditions and disorders using such
compounds and compositions.
[0004] 2. Description of Related Technology
[0005] Nicotinic acetylcholine receptors (nAChRs), belonging to the
super family of ligand gated ion channels (LGIC), are widely
distributed throughout the central nervous system (CNS) and the
peripheral nervous system (PNS), and gate the flow of cations,
controlled by acetylcholine (ACh). The nAChRs can be divided into
nicotinic receptors of the muscular junction (NMJ) and neuronal
nAChRs or neuronal nicotinic receptors (NNRs). The NNRs are
understood to play an important role in regulating CNS function and
the release of many neurotransmitters, including, but not
necessarily limited to acetylcholine, norepinephrine, dopamine,
serotonin and GABA. Consequently, nicotinic receptors mediate a
very wide range of physiological effects, and have been targeted
for therapeutic treatment of disorders relating to cognitive
function, learning and memory, neurodegeneration, pain and
inflammation, psychosis and sensory gating, mood and emotion, among
others.
[0006] Many subtypes of NNRs exist in the CNS and periphery. Each
subtype has a different effect on regulating the overall
physiological function.
[0007] Typically, NNRs are ion channels that are constructed from a
pentameric assembly of subunit proteins. Sixteen subunits of nAChRs
have been reported to date, which are identified as
.alpha.2-.alpha.10, .beta.1-.beta.4, .gamma., .delta., and
.epsilon.. Of these subunits, nine subunits, .alpha.2 through
.alpha.7 and .beta.2 through .beta.4, prominently exist in the
mammalian brain. Multiple functionally distinct nAChR complexes
also exist, for example five .alpha.7 subunits can form a receptor
as a homomeric functional pentamer or combinations of different
subunits can complex together as in the case of .alpha.4.beta.2 and
.alpha.3.beta.4 receptors (see for example, Vincler, M., McIntosh,
J. M., Targeting the .alpha.9.alpha.10 nicotinic acetylcholine
receptor to treat severe pain, Exp. Opin. Ther. Targets, 2007, 11
(7): 891-897; Paterson, D. and Nordberg, A., Neuronal nicotinic
receptors in the human brain, Prog. Neurobiol. 2000, 61: 75-111;
Hogg, R. C., Raggenbass, M., Bertrand, D., Nicotinic acetylcholine
receptors: from structure to brain function, Rev. Physiol.,
Biochem. Pharmacol., 2003, 147: 1-46; Gotti, C., Clementi, F.,
Neuronal nicotinic receptors: from structure to pathology, Prog.
Neurobiol., 2004, 74: 363-396). These subunits provide for a great
variety of homomeric and heteromeric combinations that account for
the diverse receptor subtypes.
[0008] The NNRs, in general, are involved in various cognitive
functions, such as learning, memory, attention, and therefore in
CNS disorders, i.e., Alzheimer's disease (AD), Parkinson's disease
(PD), attention deficit hyperactivity disorder (ADHD), Tourette's
syndrome, schizophrenia, bipolar disorder, pain, and tobacco
dependence (see for example, Keller, J. J., Keller, A. B., Bowers,
B. J., Wehner, J. M., Performance of alpha7 nicotinic receptor null
mutants is impaired in appetitive learning measured in a signaled
nose poke task, Behav. Brain Res., 2005, 162: 143-52; Gundish, D.,
Nicotinic acetylcholine receptor ligands as potential therapeutics,
Expert Opin. Ther. Patents, 2005, 15 (9): 1221-1239; De Luca, V.,
Likhodi, O., Van Tol, H. H., Kennedy, J. L., Wong, A. H.,
Regulation of alpha7-nicotinic receptor subunit and alpha7-like
gene expression in the prefrontal cortex of patients with bipolar
disorder and schizophrenia, Acta Psychiatr. Scand., 2006, 114:
211-5).
[0009] The homomeric .alpha.7 receptor is one of the most abundant
nicotinic receptors, along with .alpha.4.beta.2 receptors, in the
human brain, wherein it is heavily expressed in the hippocampus,
cortex, thalamic nuclei, ventral tegmental area and substantia
nigra (see for example, Broad, L. M., Sher, E., Astles, P. C.,
Zwart, R., O'Neill, M. J., Selective .alpha.7 nicotinic
acetylcholine receptor ligands for the treatment of
neuropsychiatric diseases, Drugs of the Future, 2007, 32(2):
161-170).
[0010] The role of .alpha.7 NNRs in neuronal signaling in the CNS
also has been actively investigated (see for example, Couturier,
S., Bertrand, D., Matter, J. M., Hernandez, M. C., Bertrand, S.,
Millar, N., Valera, S., Barkas, T., Ballivet, M., A neuronal
nicotinic acetylcholine receptor subunit (alpha 7) is
developmentally regulated and forms a homo-oligomeric channel
blocked by alpha-BTX, Neuron, 1990, 5: 847-56). The .alpha.7 NNRs
have been demonstrated to regulate interneuron excitability,
modulate the release of excitatory and inhibitory
neurotransmitters, and lead to neuroprotective effects in
experimental in vitro models of cellular damage (see for example,
Alkondon, M., Albuquerque, E. X., The nicotinic acetylcholine
receptor subtypes and their function in the hippocampus and
cerebral cortex, Prog. Brain Res., 2004, 145: 109-20).
[0011] Biophysical studies have shown that ion channels comprised
of .alpha.7 subunits, when expressed in heterologous expression
systems, activate and desensitize rapidly, and furthermore, exhibit
relatively higher calcium permeability compared to other NNR
combinations (see for example, Dajas-Bailador, F., Wonnacott, S.,
Nicotinic acetylcholine receptors and the regulation of neuronal
signaling, Trends Pharmacol. Sci., 2004, 25: 317-24).
[0012] The NNR ligands have been also implicated in smoking
cessation, weight control and as potential analgesics (see for
example, Balbani, A. P. S., Montovani, J. C., Recent developments
for smoking cessation and treatment of nicotine dependence, Exp.
Opin. Ther. Patents, 2003, 13 (7): 287-297; Gurwitz, D., The
therapeutic potential of nicotine and nicotinic agonists for weight
control, Exp. Opin. Invest. Drugs, 1999, 8(6): 747-760; Vincler,
M., Neuronal nicotinic receptors as targets for novel analgesics,
Exp. Opin. Invest. Drugs, 2005, 14 (10): 1191-1198; Bunnelle, W.
H., Decker, M. W., Neuronal nicotinic acetylcholine receptor
ligands as potential analgesics, Exp. Opin. Ther. Patents, 2003, 13
(7): 1003-1021; Decker, M. W., Meyer, M. D., Sullivan, J. P., The
therapeutic potential of nicotinic acetylcholine receptor agonists
for pain control, Exp. Opin. Invest. Drugs, 2001, 10 (10):
1819-1830; Vincler, M., McIntosh, J. M., Targeting the math
nicotinic acetylcholine receptor to treat severe pain, Exp. Opin.
Ther. Targets, 2007, 11 (7): 891-897).
[0013] The .alpha.7 and .alpha.4.beta.2 NNRs have been shown to
play a significant role in enhancing cognitive function, including
aspects of learning, memory and attention (Levin, E. D., J.
Neurobiol. 53: 633-640, 2002). For example, .alpha.7 NNRs have been
linked to conditions and disorders related to attention deficit
disorder, ADHD, AD, mild cognitive impairment, senile dementia,
dementia associated with Lewy bodies, dementia associated with
Down's syndrome, AIDS dementia, Pick's disease, as well as
cognitive deficits associated with schizophrenia (CDS), among other
systemic activities. The .alpha.4.beta.2 receptor subtype is
implicated in attention, cognition, epilepsy, and pain control
(Paterson, D. and Nordberg, A., Neuronal nicotinic receptors in the
human brain, Prog. Neurobiol. 2000, 61: 75-111).
[0014] Certain compounds, like the plant alkaloid nicotine,
interact with all known subtypes of the nAChRs, accounting for the
profound physiological effects of this compound. Nicotine is known
to provide enhanced attention and cognitive performance, reduced
anxiety, enhanced sensory gating, and analgesia and neuroprotective
effects when administered. Such effects are mediated by the
non-selective effect of nicotine at a variety of nicotinic receptor
subtypes. However, nicotine also produces adverse consequences,
such as cardiovascular and gastrointestinal problems that interfere
at therapeutic doses, and its addictive nature and acute toxicity
are well-known. Accordingly, there is a need to identify
subtype-selective compounds that evoke the beneficial effects of
nicotine while eliminating or decreasing adverse effects.
[0015] The activity at the NNRs can be modified or regulated by the
administration of subtype selective NNR ligands. The ligands can
exhibit antagonist, agonist, or partial agonist properties and thus
have potential in treatment of various cognitive disorders.
[0016] Although compounds that nonselectively demonstrate activity
at a range of nicotinic receptor subtypes including the
.alpha.4.beta.2 and .alpha.7 NNRs are known, it would be beneficial
to provide compounds that interact selectively with
.alpha.7-containing neuronal NNRs, .alpha.4.beta.2 NNRs, or both
.alpha.7 and .alpha.4.beta.2 NNRs compared to other subtypes.
SUMMARY OF THE INVENTION
[0017] The invention is directed to 4-substituted azaadamantane
derivatives as well as compositions comprising such compounds, and
method of using the same.
[0018] One aspect of the invention relates to a compound of formula
(I)
##STR00001##
[0019] wherein
[0020] Y.sup.1 is a bond, --N(R.sup.X)--C(O)--, --O--,
--N(R.sup.X)--C(O)--N(R.sup.Y)--, --O--C(O)--, or --N(R.sup.Z)--;
wherein the --C(O) moiety of --N(R.sup.X)--C(O)-- and --O--C(O)--
are attached to A of formula (I);
[0021] A is aryl, heteroaryl, heterocycle, cycloalkyl,
cycloalkenyl, arylalkyl, heteroarylalkyl, heterocyclealkyl,
cycloalkylalkyl, or cycloalkenylalkyl; and
[0022] R.sup.X, R.sup.Y, and R.sup.Z, at each occurrence, are each
independently hydrogen, alkyl, or haloalkyl;
[0023] or a pharmaceutically acceptable salt, amide, ester or
prodrug thereof.
[0024] Another aspect of the invention relates to pharmaceutical
compositions comprising compounds of the invention. Such
compositions can be administered in accordance with a method of the
invention, typically as part of a therapeutic regimen for treatment
or prevention of conditions and disorders related to NNR activity,
and more particularly .alpha.7 NNR activity, .alpha.4.beta.2 NNR
activity, or both .alpha.7 NNR activity and .alpha.4.beta.2 NNR
activity.
[0025] A further aspect of the invention relates to a method of
modulating .alpha.7 NNR activity, .alpha.4.beta.2 NNR activity, or
both .alpha.7 NNR activity and .alpha.4.beta.2 NNR activity. The
method is useful for treating, preventing, or both treating and
preventing conditions and disorders related to .alpha.7 NNR
activity, .alpha.4.beta.2 NNR activity, or both .alpha.7 NNR
activity and .alpha.4.beta.2 NNR activity in mammals. More
particularly, the method is useful for conditions and disorders
related to attention deficit disorder, ADHD, AD, Parkinson's
disease, Tourette's syndrome, schizophrenia, cognitive deficits of
schizophrenia (CDS), mild cognitive impairment, age-associated
memory impairment (AAMI), senile dementia, AIDS dementia, Pick's
disease, dementia associated with Lewy bodies, dementia associated
with Down's syndrome, amyotrophic lateral sclerosis, Huntington's
disease, diminished CNS function associated with traumatic brain
injury, acute pain, post-surgical pain, chronic pain, inflammatory
pain, neuropathic pain, smoking cessation, ischemia, sepsis, wound
healing, and other complications associated with diabetes, among
other systemic and neuroimmunomodulatory activities.
[0026] Radiolabelled compounds useful for evaluating the binding
affinity of substituted azaadamantane derivatives to .alpha.7
nicotinic acetylcholine receptors also are described herein.
[0027] The compounds, compositions comprising the compounds, and
methods for treating or preventing conditions and disorders by
administering the compounds are further described herein.
DETAILED DESCRIPTION OF THE INVENTION
Definition of Terms
[0028] For a variable that occurs more than one time in any
substituent or in the compound of the invention or any other
formulae herein, its definition on each occurrence is independent
of its definition at every other occurrence. Combinations of
substituents are permissible only if such combinations result in
stable compounds. Stable compounds are compounds which can be
isolated in a useful degree of purity from a reaction mixture.
[0029] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0030] The term "alkenyl" as used herein, means a straight or
branched hydrocarbon chain containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0031] The term "alkyl" as used herein, means a straight or
branched, saturated hydrocarbon chain containing from 1 to 10
carbon atoms, including lower alkyl, C.sub.1-6 alkyl and C.sub.1-3
alkyl. The term "lower alkyl" or "C.sub.1-6 alkyl" means a straight
or branched chain hydrocarbon containing 1 to 6 carbon atoms. The
term "C.sub.1-3 alkyl" means a straight or branched chain
hydrocarbon containing 1 to 3 carbon atoms. Representative examples
of alkyl include, but are not limited to, methyl, ethyl, n-propyl,
iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,
isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,
2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
[0032] The term "alkylene" denotes a divalent group derived from a
straight or branched chain hydrocarbon of from 1 to 10 carbon
atoms. Representative examples of alkylene include, but are not
limited to, --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
and --CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0033] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0034] The term "aryl" as used herein, means phenyl, a bicyclic
aryl, or a tricyclic aryl. The bicyclic aryl is naphthyl, or a
phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a
monocyclic cycloalkenyl. Representative examples of the aryl groups
include, but are not limited to, dihydroindenyl, indenyl, naphthyl,
dihydronaphthalenyl, and tetrahydronaphthalenyl. The tricyclic aryl
is a bicyclic aryl fused to a monocyclic cycloalkyl, or a bicyclic
aryl fused to a monocyclic cycloalkenyl, or a bicyclic aryl fused
to a phenyl. Representative examples of tricyclic aryl ring
include, but are not limited to, anthracene, phenanthrene,
dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl. The
aryl groups of the present invention can be unsubstituted or
substituted and are attached to the parent molecular moiety through
any carbon atom contained within the ring systems.
[0035] The term "arylalkyl" as used herein, means an aryl group, as
defined herein, appended to the parent molecular moiety through an
alkyl group, as defined herein. Representative examples of
arylalkyl include, but are not limited to, benzyl (phenylmethyl),
2-phenylethyl, and 3-phenylpropyl.
[0036] The term "cyano" as used herein, means a --CN group.
[0037] The term "cyanoalkyl" as used herein, means a cyano group,
as defined herein, appended to the parent molecular moiety through
an alkyl group, as defined herein. Representative examples of
cyanoalkyl include, but are not limited to, cyanomethyl,
2-cyanoethyl, and 3-cyanopropyl.
[0038] The term "cycloalkyl" or "cycloalkane" as used herein, means
a monocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocyclic
cycloalkyl is a saturated hydrocarbon ring system having three to
eight carbon atoms, zero heteroatoms and zero double bonds. The
monocyclic cycloalkyl can be attached to the parent molecular
moiety through any substitutable atom contained within the
monocyclic cycloalkyl. Examples of monocyclic ring systems include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl
fused to a monocyclic cycloalkyl ring, or a bridged monocyclic ring
system in which two non-adjacent carbon atoms of the monocyclic
ring are linked by an alkylene bridge containing one, two, or three
carbon atoms. Representative examples of bicyclic ring systems
include, but are not limited to, bicyclo[3.1.1]heptane,
bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,
bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic
cycloalkyls are exemplified by a bicyclic cycloalkyl fused to a
monocyclic cycloalkyl, or a bridged bicyclic cycloalkyl in which
two non-adjacent carbon atoms of the bicyclic ring system are
linked by an alkylene bridge of between one and four carbon atoms.
Representative examples of tricyclic-ring systems include, but are
not limited to, tricyclo[3.3.1.0.sup.3,7]nonane and
tricyclo[3.3.1.1.sup.3,7]decane (adamantane). The mono cyclic,
bicyclic, and tricyclic cycloalkyls can be unsubstituted or
substituted, and are attached to the parent molecular moiety
through any substitutable atom contained within the ring
systems.
[0039] The term "cycloalkylalkyl" as used herein, means a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, and cyclohexylmethyl.
[0040] The term "cycloalkenyl" or "cycloalkene" as used herein,
means a monocyclic or a bicyclic hydrocarbon ring system. The
monocyclic cycloalkenyl has four, five, six, seven or eight carbon
atoms and zero heteroatoms. The four-membered ring systems have one
double bond, the five- or six-membered ring systems have one or two
double bonds, and the seven- or eight-membered ring systems have
one, two or three double bonds. Representative examples of
monocyclic cycloalkenyl groups include, but are not limited to,
cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and
cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic
cycloalkenyl fused to a monocyclic cycloalkyl group, or a
monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.
The monocyclic or bicyclic cycloalkenyl ring may contain one or two
alkylene bridges, each consisting of one, two, three, or four
carbon atoms and each linking two non-adjacent carbon atoms of the
ring. Representative examples of the bicyclic cycloalkenyl groups
include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene,
octahydronaphthalenyl and 1,6-dihydro-pentalene. The monocyclic and
bicyclic cycloalkenyl groups of the present invention can be
unsubstituted or substituted, and are attached to the parent
molecular moiety through any substitutable atom contained within
the ring systems.
[0041] The term "cycloalkenylalkyl" as used herein, means a
cycloalkenyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0042] The term "ethylenedioxy" as used herein, means a
--O--(CH.sub.2).sub.2--O-- group wherein the oxygen atoms of the
ethylenedioxy group are attached to two adjacent carbon atoms of a
phenyl or naphthyl moiety, forming a six membered ring with the two
adjacent carbon atoms of the phenyl or naphthyl moiety that it is
attached to.
[0043] The term "halo" or "halogen" as used herein, means --Cl,
--Br, --I, or --F.
[0044] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five or six
hydrogen atoms are replaced by halogen. Representative examples of
haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,
and 2-chloro-3-fluoropentyl.
[0045] The term "heteroaryl" as used herein, means a monocyclic
heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a
five- or six-membered ring. The five-membered ring contains two
double bonds. The five membered ring may contain one heteroatom
selected from O or S; or four nitrogen atoms; or one, two, or three
nitrogen atoms and optionally one oxygen or sulfur atom. The
six-membered ring contains three double bonds and one, two, three
or four nitrogen atoms. Representative examples of monocyclic
heteroaryl include, but are not limited to, furanyl, imidazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,
tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and
triazinyl. The bicyclic heteroaryl is exemplified by a monocyclic
heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a
monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a
monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a
monocyclic heteroaryl, or a monocyclic heteroaryl fused to a
monocyclic heterocycle. Representative examples of bicyclic
heteroaryl groups include, but not limited to, benzofuranyl,
benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,
6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,
indolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
pyridoimidazolyl, quinolinyl, thiazolo[5,4-b]pyridin-2-yl,
thiazolo[5,4-d]pyrimidin-2-yl, thieno[2,3-c]pyridinyl, and
5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic
heteroaryl groups of the present invention can be substituted or
unsubstituted, and are connected to the parent molecular moiety
through any substitutable carbon atom or any substitutable nitrogen
atom contained within the ring systems.
[0046] The term "heteroarylalkyl" as used herein, means a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0047] The term "heteroatom" as used herein, means a nitrogen,
oxygen, or sulfur atom.
[0048] The term "heterocycle" or "heterocyclic" as used herein,
means a monocyclic, a bicyclic, or a tricyclic heterocycle ring
system, provided that the heterocycle is not 1,3-benzodioxolyl,
2,3-dihydro-1,4-benzodioxine, naphtho[2,3-d][1,3]dioxole, or
2,3-dihydronaphtho[2,3-b][1,4]dioxine. The monocyclic heterocycle
is a three-, four-, five-, six-, or seven-membered ring containing
at least one heteroatom independently selected from the group
consisting of O, N, and S. The three- or four-membered ring
contains zero or one double bond, and one heteroatom selected from
the group consisting of O, N, and S. The five-membered ring
contains zero or one double bond and one, two or three heteroatoms
selected from the group consisting of O, N and S. The six-membered
ring contains zero, one or two double bonds and one, two, or three
heteroatoms selected from the group consisting of O, N, and S. The
seven-membered ring contains zero, one, two, or three double bonds
and one, two, or three heteroatoms selected from the group
consisting of O, N, and S. Representative examples of monocyclic
heterocycles include, but are not limited to, azetidinyl, azepanyl,
aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl,
1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl,
isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl,
morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,
oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,
pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydrothienyl, tetrahydropyranyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl,
and trithianyl. The bicyclic heterocycle is a monocyclic
heterocycle fused to a phenyl group, or a monocyclic heterocycle
fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused
to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to
a monocyclic heterocycle, or a bridged monocyclic heterocycle ring
system in which two non adjacent atoms of the ring are linked by an
alkylene bridge containing one, two, three, or four carbon atoms.
Representative examples of bicyclic heterocycles include, but are
not limited to, benzopyranyl, benzothiopyranyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, and
2,3-dihydro-1H-indolyl. Tricyclic heterocycles are exemplified by a
bicyclic heterocycle fused to a phenyl group, or a bicyclic
heterocycle fused to a monocyclic cycloalkyl, or a bicyclic
heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic
heterocycle fused to a monocyclic heterocycle, or a bridged
bicyclic heterocycle in which two non adjacent atoms of the
bicyclic ring are linked by an alkylene bridge consisting of one,
two, three, or four carbon atoms. An example of a tricyclic
heterocycle is aza-admantane such as
1-azatricyclo[3.3.1.1.sup.3,7]decane. The monocyclic, bicyclic and
tricyclic heterocycles are connected to the parent molecular moiety
through any substitutable carbon or nitrogen atom contained within
the ring systems, and can be unsubstituted or substituted.
[0049] The term "heterocyclealkyl" as used herein, means a
heterocycle, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0050] The term "methylenedioxy" as used herein, means a
--O--(CH.sub.2)--O-- group wherein the oxygen atoms of the
methylenedioxy group are attached to two adjacent carbon atoms of
the phenyl or naphthyl ring, forming a five membered ring with the
two adjacent carbon atoms of the phenyl or naphthyl moiety that it
is attached to.
[0051] The term "oxo" as used herein, means a .dbd.O group.
[0052] The term "parenterally," as used herein, refers to modes of
administration, including intravenous, intramuscular,
intraperitoneal, intrasternal, subcutaneous, intraarticular
injection and infusion.
[0053] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which can serve as
pharmaceutically acceptable carriers are sugars such as lactose,
glucose and sucrose; starches such as corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; cocoa butter and suppository
waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive oil, corn oil and soybean oil; glycols; such a
propylene glycol; esters such as ethyl oleate and ethyl laurate;
agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide; alginic acid; pyrogen-free water; isotonic saline;
Ringer's solution; ethyl alcohol; and phosphate buffer solutions;
as well as other non-toxic compatible lubricants such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of one
skilled in the art of formulations.
[0054] The term "pharmaceutically acceptable salts, esters and
amides" as used herein, include salts, zwitterions, esters and
amides of compounds of formula (I) which are, within the scope of
sound medical judgment, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response, and the like, are commensurate with
a reasonable benefit/risk ratio, and are effective for their
intended use.
[0055] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well-known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention or separately by
reacting a free base functional group with a suitable organic
acid.
[0056] Representative acid addition salts include, but are not
limited to acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate,
maleate, malate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate, and undecanoate.
[0057] The term "pharmaceutically acceptable prodrug" or "prodrug,"
as used herein, represents those prodrugs of the compounds of the
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use.
[0058] The term "tautomer" as used herein means a proton shift from
one atom of a compound to another atom of the same compound wherein
two or more structurally distinct compounds are in equilibrium with
each other.
[0059] The terms "unsubstituted or substituted" with reference to
aryl, cycloalkyl, cycloalkenyl, heterocycle, or heteroaryl moieties
of this invention, as a substituent, or as part of a substituent,
each independently, as used herein mean unsubstituted or
substituted with 1, 2, 3, 4, or 5 substituents as described
hereinbelow, unless otherwise noted. The optional substituents are
selected from the group consisting of alkyl, alkenyl, alkynyl,
halogen, cyano, oxo, methylenedioxy, ethylenedioxy, -G.sup.1,
--NO.sub.2, --OR.sup.1a, --OC(O)R.sup.1a,
--OC(O)N(R.sup.b)(R.sup.3a), --SR.sup.1a, --S(O).sub.2R.sup.2a,
--S(O).sub.2N(R.sup.b)(R.sup.3a), --C(O)R.sup.1a, --C(O)OR.sup.1a,
--C(O)N(R.sup.b)(R.sup.3a), --N(R.sup.b)(R.sup.3a),
--N(R.sup.a)C(O)R.sup.1a, --N(R.sup.a)S(O).sub.2R.sup.2a,
--N(R.sup.a)C(O)O(R.sup.1a), --N(R.sup.a)C(O)N(R.sup.b)(R.sup.3a),
--(CR.sup.4aR.sup.5a).sub.m--NO.sub.2,
--(CR.sup.4aR.sup.5a).sub.m--OR.sup.1a,
--(CR.sup.4aR.sup.5a).sub.m--OC(O)R.sup.1a,
--(CR.sup.4aR.sup.5a).sub.m--OC(O)N(R.sup.b)(R.sup.3a),
--(CR.sup.4aR.sup.5a).sub.m--SR.sup.1a,
--(CR.sup.4aR.sup.5a).sub.m--S(O).sub.2R.sup.2a,
--(CR.sup.4aR.sup.5a).sub.m--S(O).sub.2N(R.sup.b)(R.sup.3a),
--(CR.sup.4aR.sup.5a).sub.m--C(O)R.sup.1a,
--(CR.sup.4aR.sup.5a).sub.m--C(O)OR.sup.1a,
--(CR.sup.4aR.sup.5a).sub.m--C(O)N(R.sup.b)(R.sup.3a),
--(CR.sup.4aR.sup.5a).sub.m--N(R.sup.b)(R.sup.3a),
--(CR.sup.4aR.sup.5a).sub.m--N(R.sup.a)C(O)R.sup.1a,
--(CR.sup.4aR.sup.5a).sub.m--N(R.sup.a)S(O).sub.2R.sup.2a,
--(CR.sup.4aR.sup.5a).sub.m--N(R.sup.a)C(O)O(R.sup.1a),
--(CR.sup.4aR.sup.5a).sub.m--N(R.sup.a)C(O)N(R.sup.b)(R.sup.3a),
--(CR.sup.4aR.sup.5a).sub.m-G.sup.1, cyanoalkyl, and haloalkyl;
wherein
[0060] R.sup.1a and R.sup.3a, at each occurrence, are each
independently hydrogen, alkyl, haloalkyl, G.sup.1, or
--(CR.sup.6R.sup.7).sub.n-G.sup.1;
[0061] R.sup.2a, at each occurrence, is independently alkyl,
haloalkyl, G.sup.1, or --(CR.sup.6R.sup.7).sub.n-G.sup.1;
[0062] R.sup.4a, R.sup.5a, R.sup.6, and R.sup.7, at each
occurrence, are each independently hydrogen, halogen, alkyl, or
haloalkyl;
[0063] R.sup.a and R.sup.b, at each occurrence, are each
independently hydrogen, alkyl, or haloalkyl;
[0064] m and n, at each occurrence, are each independently 1, 2, 3,
4, or 5;
[0065] G.sup.1 is aryl, heteroaryl, heterocycle, cycloalkyl, or
cycloalkenyl, wherein each G.sup.1 is independently unsubstituted
or substituted with 1, 2, 3, 4 or 5 substituents selected from the
group consisting of alkyl, alkenyl, alkynyl, halogen, cyano, oxo,
methylenedioxy, ethylenedioxy, --NO.sub.2, --OR.sup.1b,
--OC(O)R.sup.1b, --OC(O)N(R.sup.b)(R.sup.3b), --SR.sup.1b,
--S(O).sub.2R.sup.2b, --S(O).sub.2N(R.sup.b)(R.sup.3b),
--C(O)R.sup.1b, --C(O)OR.sup.1b, --C(O)N(R.sup.b)(R.sup.3b),
--N(R.sup.b)(R.sup.3b), --N(R.sup.a)C(O)R.sup.1b,
--N(R.sup.a)S(O).sub.2R.sup.2b, --N(R.sup.a)C(O)O(R.sup.1b),
--N(R.sup.a)C(O)N(R.sup.b)(R.sup.3b),
--(CR.sup.4bR.sup.5b).sub.m--NO.sub.2,
--(CR.sup.4bR.sup.5b).sub.m--OR.sup.1b,
--(CR.sup.4bR.sup.5b).sub.m--OC(O)R.sup.1b,
--(CR.sup.4bR.sup.5b).sub.m--OC(O)N(R.sup.b)(R.sup.3b),
--(CR.sup.4bR.sup.5b).sub.m--SR.sup.1b,
--CR.sup.4bR.sup.5b).sub.m--S(O).sub.2R.sup.2b,
--(CR.sup.4bR.sup.5b).sub.m--S(O).sub.2N(R.sup.b)(R.sup.3b),
--(CR.sup.4bR.sup.5b).sub.m--C(O)R.sup.1b,
--(CR.sup.4bR.sup.5b).sub.m--C(O)OR.sup.1b,
--(CR.sup.4bR.sup.5b).sub.m--C(O)N(R.sup.b)(R.sup.3b),
--(CR.sup.4bR.sup.5b).sub.m--N(R.sup.b)(R.sup.3b),
--(CR.sup.4bR.sup.5b).sub.m--N(R.sup.a)C(O)R.sup.1b,
--(CR.sup.4bR.sup.5b).sub.m--N(R.sup.a)S(O).sub.2R.sup.2b,
--(CR.sup.4bR.sup.5b).sub.m--N(R.sup.a)C(O)O(R.sup.1b),
--(CR.sup.4bR.sup.5b).sub.m--N(R.sup.a)C(O)N(R.sup.b)(R.sup.3b),
cyanoalkyl, and haloalkyl;
[0066] R.sup.1b and R.sup.3b, at each occurrence, are each
independently hydrogen, alkyl, or haloalkyl;
[0067] R.sup.2b, at each occurrence, is independently alkyl or
haloalkyl; and
[0068] R.sup.4b and R.sup.5b, at each occurrence, are each
independently hydrogen, halogen, alkyl, or haloalkyl.
Compounds of the Invention
[0069] One aspect of the invention relates to a compound of formula
(I)
##STR00002##
[0070] wherein
[0071] Y.sup.1 is a bond, --N(R.sup.X)--C(O)--, --O--,
--N(R.sup.X)--C(O)--N(R.sup.Y)--, --O--C(O)--, or
--N(R.sup.Z)--;
[0072] A is unsubstituted or substituted aryl, heteroaryl,
heterocycle, cycloalkyl, cycloalkenyl, arylalkyl, heteroarylalkyl,
heterocyclealkyl, cycloalkylalkyl, or cycloalkenylalkyl; and
[0073] R.sup.X, R.sup.Y, and R.sup.Z, at each occurrence, are each
independently hydrogen, alkyl, or haloalkyl;
[0074] or a pharmaceutically acceptable salt, amide or prodrug
thereof.
[0075] In another embodiment, the invention relates to compounds of
formula (I), wherein Y.sup.1 is attached to A of formula (I)
through --C(O) moiety, when Y.sup.1 is --N(R.sup.X)--C(O)-- or
--O--C(O)--, or pharmaceutically acceptable salts, amides and
prodrugs thereof.
[0076] In one embodiment, the invention relates to compounds of
formula (I), wherein Y.sup.1 is --N(R.sup.X)--C(O)-- and R.sup.X is
hydrogen, alkyl, or haloalkyl, or pharmaceutically acceptable
salts, amides and prodrugs thereof. One particular example of
R.sup.X is hydrogen.
[0077] In another embodiment, the invention relates to compounds of
formula (I), wherein Y.sup.1 is --O--. In yet another embodiment,
Y.sup.1 is --N(R.sup.X)--C(O)--N(R.sup.Y)--, and R.sup.X and
R.sup.Y are each independently hydrogen, alkyl, or haloalkyl, or
pharmaceutically acceptable salts, amides and prodrugs thereof.
Particular examples of R.sup.X and R.sup.Y are hydrogen.
[0078] In another embodiment, the invention relates to compounds of
formula (I), wherein Y.sup.1 is --O--C(O)--, or pharmaceutically
acceptable salts, amides and prodrugs thereof. In another
embodiment, the invention relates to compounds of formula (I),
wherein Y.sup.1 is --N(R.sup.Z)-- and R.sup.Z is hydrogen, alkyl,
or haloalkyl, or pharmaceutically acceptable salts, amides and
prodrugs thereof. One particular example of R.sup.Z is
hydrogen.
[0079] In one embodiment, the invention relates to compounds of
formula (I), wherein A is aryl (for example, phenyl or naphthyl) or
heteroaryl (for example, indolyl or pyridinyl), each of which is
independently unsubstituted or substituted, or pharmaceutically
acceptable salts, amides and prodrugs thereof.
[0080] In another embodiment, the invention relates to compounds of
formula (I), wherein A is arylalkyl (for example, benzyl or
naphthylmethyl) or heteroarylalkyl (for example, pyridinylmethyl or
indolylmethyl) wherein the aryl moiety of the arylalkyl and the
heteroaryl moiety of the heteroarylalkyl are each independently
unsubstituted or substituted, or pharmaceutically acceptable salts,
amides or prodrugs thereof.
[0081] One aspect of the invention relates to compounds of formula
(I), wherein Y.sup.1 is --N(R.sup.X)--C(O)--, A is aryl or
heteroaryl, and R.sup.X is hydrogen, alkyl, or haloalkyl, or
pharmaceutically acceptable salts, amides and prodrugs thereof. Of
this group of compounds, examples of a subgroup include those
wherein R.sup.X is hydrogen.
[0082] Another aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --N(R.sup.X)--C(O)--, A is
arylalkyl or heteroarylalkyl, and R.sup.X is hydrogen, alkyl, or
haloalkyl, or pharmaceutically acceptable salts, amides and
prodrugs thereof. Of this group of compounds, examples of a
subgroup include those wherein R.sup.X is hydrogen.
[0083] Yet another aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --O--, A is aryl or heteroaryl, or
pharmaceutically acceptable salts, amides and prodrugs thereof.
[0084] Yet another aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --O--, A is arylalkyl or
heteroarylalkyl, or pharmaceutically acceptable salts, amides and
prodrugs thereof.
[0085] A further aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --N(R.sup.X)--C(O)--N(R.sup.Y)--, A
is aryl or heteroaryl, and R.sup.X and R.sup.Y are each
independently hydrogen, alkyl, or haloalkyl, or pharmaceutically
acceptable salts, amides and prodrugs thereof. Of this group of
compounds, examples of a subgroup include those wherein R.sup.X and
R.sup.Y are hydrogen.
[0086] Yet another aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --N(R.sup.X)--C(O)--N(R.sup.Y)--, A
is arylalkyl or heteroarylalkyl, and R.sup.X and R.sup.Y are each
independently hydrogen, alkyl, or haloalkyl, or pharmaceutically
acceptable salts, amides and prodrugs thereof. Of this group of
compounds, examples of a subgroup include those wherein R.sup.X and
R.sup.Y are hydrogen.
[0087] Yet another aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --N(R.sup.Z)--, A is aryl or
heteroaryl, and R.sup.Z is hydrogen, alkyl, or haloalkyl, or
pharmaceutically acceptable salts, amides and prodrugs thereof. Of
this group of compounds, examples of a subgroup include those
wherein R.sup.Z is hydrogen.
[0088] Yet another aspect of the invention relates to compounds of
formula (I), wherein Y.sup.1 is --N(R.sup.Z)--, A is arylalkyl or
heteroarylalkyl, and R.sup.Z is hydrogen, alkyl, or haloalkyl, or
pharmaceutically acceptable salts, amides, esters, and prodrugs
thereof. Of this group of compounds, examples of a subgroup include
those wherein R.sup.Z is hydrogen.
[0089] Exemplary compounds of formula (I) include, but are not
limited to: [0090] 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-2-naphthyloxime; [0091] 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(pentafluorobenzyl)oxime; [0092]
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-(4-chlorophenyl)oxime;
[0093] 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(6-chloropyridin-3-yl)oxime; [0094]
N'-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylidene-1H-indole-3-carbohy-
drazide; and [0095] 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-benzyloxime.
[0096] or pharmaceutically acceptable salts, amides or prodrugs
thereof.
[0097] Compounds disclosed herein may contain asymmetrically
substituted carbon or sulfur atoms, and accordingly may exist in,
and be isolated as, single stereoisomers (e.g. single enantiomer or
single diastereomer), mixtures of stereoisomers (e.g. any mixture
of enantiomers or diastereomers) or racemic mixtures thereof.
Individual optically-active forms of the compounds can be prepared
for example, by synthesis from optically-active starting materials,
by chiral synthesis, by enzymatic resolution, by biotransformation,
or by chromatographic separation. It is to be understood that the
present invention encompasses any racemic, optically-active,
stereoisomeric form, or mixtures of various proportions thereof,
which form possesses properties useful in the modulation of NNRs
activity, particularly .alpha.7NNRs, .alpha.4.beta.2, or both
.alpha.7 and .alpha.4.beta.2. Where the stereochemistry of the
chiral centers present in the chemical structures illustrated
herein is not specified, the chemical structure is intended to
encompass compounds containing either configuration of each chiral
center, and mixtures thereof.
[0098] Geometric isomers can exist in the present compounds. The
invention contemplates the various geometric isomers and mixtures
thereof resulting from the disposition of substituents around a
carbon-carbon double bond, a carbon nitrogen double bond, a
cycloalkyl group, or a heterocycloalkyl group. Substituents around
a carbon-carbon or carbon-nitrogen double bond are designated as
being of Z or E configuration and substituents around a cycloalkyl
or heterocycle are designated as being of cis or trans
configuration.
[0099] For example, compounds of the invention can exist in the
forms represented by formulas (Ia) and (Ib):
##STR00003##
One skilled in the art will recognize that formulas (Ia) and (Ib)
represent enantiomers when a chiral center is not present on
--Y.sup.1-A. However, when --Y.sup.1-A does contain one or more
asymmetric centers, the geometric isomers about the C.dbd.N bond
will be diastereomers.
[0100] It is to be understood that formula (I) includes formula
(Ia), (Ib), or mixtures of both in various ratios. Thus, compounds
of formula (Ia), (Ib), or mixtures of both in various proportions
are useful in modulating the effects of NNRs, and more particularly
.alpha.7 NNRs, .alpha.4.beta.2 NNRs, or both .alpha.7 and
.alpha.4.beta.2 NNRs.
[0101] It is to be understood that compounds disclosed herein may
exhibit the phenomenon of tautomerism.
[0102] The compounds within this specification may be represented
only by one of the possible tautomeric, geometric or stereoisomeric
forms in naming of the compounds or formulae drawings. However, it
is to be understood that the invention encompasses any tautomeric,
geometric or stereoisomeric forms, and mixtures thereof, and is not
to be limited merely to any one tautomeric, geometric or
stereoisomeric form utilized within the naming of the compounds or
formulae drawings.
Amides, Esters and Prodrugs
[0103] Prodrugs are pharmacologically inactive derivatives of an
active drug designed to ameliorate some identified, undesirable
physical or biological property. The physical properties are
usually solubility (too much or not enough lipid or aqueous
solubility) or stability related, while problematic biological
properties include too rapid metabolism or poor bioavailability
which itself may be related to a physicochemical property.
[0104] Prodrugs are usually prepared by: a) formation of ester,
hemi esters, carbonate esters, nitrate esters, amides, hydroxamic
acids, carbamates, imines, Mannich bases, and enamines of the
active drug, b) functionalizing the drug with azo, glycoside,
peptide, and ether functional groups, c) use of polymers, salts,
complexes, phosphoramides, acetals, hemiacetals, and ketal forms of
the drug. For example, see Andrejus Korolkovas's, "Essentials of
Medicinal Chemistry", John Wiley-Interscience Publications, John
Wiley and Sons, New York (1988), pp. 97-118, which is incorporated
herein in its entirety by reference.
[0105] Esters can be prepared from substrates of formula (I)
containing either a hydroxyl group or a carboxy group by general
methods known to persons skilled in the art. The typical reactions
of these compounds are substitutions replacing one of the
heteroatoms by another atom, for example:
##STR00004##
[0106] Amides can be prepared from substrates of formula (I)
containing either an amino group or a carboxy group in similar
fashion. Esters can also react with amines or ammonia to form
amides.
##STR00005##
[0107] Another way to make amides from compounds of formula (I) is
to heat carboxylic acids and amines together.
##STR00006##
[0108] In Schemes 2 and 3, R and R' are independently substrates of
formula (I), alkyl or hydrogen. Various embodiments of the
invention of formula (I) that are substrates for prodrugs, amides
and esters include, but are not limited to, Example 5.
Compositions of the Invention
[0109] The invention also provides pharmaceutical compositions
comprising of compounds of the invention, or pharmaceutically
acceptable salts, amides, esters, prodrugs, or salts of prodrugs
thereof, formulated together with one or more pharmaceutically
acceptable carriers.
[0110] The compounds identified by the methods described
hereinabove may be administered as the sole pharmaceutical agent or
in combination with one or more other pharmaceutical agents where
the combination causes no unacceptable adverse effects. For
example, the compounds of this invention can be combined with an
atypical antipsychotic. Specific examples of suitable atypical
antipsychotics include, but are not limited to, clozapine,
risperidone, olanzapine, quietapine, ziprasidone, zotepine,
iloperidone, and the like. Thus, the present invention also
includes pharmaceutical compositions which are comprised of
therapeutically effective amount of compounds identified by the
methods described herein, or pharmaceutically acceptable salts,
prodrugs or salts of prodrugs thereof, one or more pharmaceutical
agents as disclosed hereinabove, and one or more pharmaceutically
acceptable carriers.
[0111] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an
oral or nasal spray. The pharmaceutical compositions can be
formulated in solid, semi-solid or liquid form, for oral
administration.
[0112] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions and sterile
powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethylene glycol, glycerol, and the like, and
suitable mixtures thereof), vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate, or suitable
mixtures thereof. Suitable fluidity of the composition may be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0113] These compositions can also contain adjuvants such as
preservative agents, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of microorganisms can
be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the
like. It also can be desirable to include isotonic agents, for
example, sugars, sodium chloride and the like. Prolonged absorption
of the injectable pharmaceutical form can be brought about by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0114] In some cases, in order to prolong the effect of a drug, it
is often desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This can be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug can depend upon its rate of dissolution, which, in turn, may
depend upon crystal size and crystalline form. Alternatively, a
parenterally administered drug form can be administered by
dissolving or suspending the drug in an oil vehicle.
[0115] Suspensions, in addition to the active compounds, can
contain suspending agents, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth, and mixtures thereof.
[0116] If desired, and for more effective distribution, the
compounds of the invention can be incorporated into slow-release or
targeted-delivery systems such as polymer matrices, liposomes, and
microspheres. They may be sterilized, for example, by filtration
through a bacteria-retaining filter or by incorporation of
sterilizing agents in the form of sterile solid compositions, which
may be dissolved in sterile water or some other sterile injectable
medium immediately before use.
[0117] Injectable depot forms are made by forming microencapsulated
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations also are prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0118] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0119] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation also can be a
sterile injectable solution, suspension or emulsion in a nontoxic,
parenterally acceptable diluent or solvent such as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that can
be employed are water, Ringer's solution, U.S.P. and isotonic
sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil can be employed including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the preparation of injectables.
[0120] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
one or more compounds of the invention is mixed with at least one
inert pharmaceutically acceptable carrier such as sodium citrate or
dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol, and salicylic acid;
b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as
glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay; and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents.
[0121] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using lactose or
milk sugar as well as high molecular weight polyethylene
glycols.
[0122] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They can optionally contain
opacifying agents and can also be of a composition that releases
the active ingredient(s) only, or preferentially, in a certain part
of the intestinal tract in a delayed manner. Examples of materials
useful for delaying release of the active agent can include
polymeric substances and waxes.
[0123] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating carriers
such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at ambient temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0124] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0125] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0126] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches. A
desired compound of the invention is admixed under sterile
conditions with a pharmaceutically acceptable carrier and any
needed preservatives or buffers as may be required. Ophthalmic
formulation, eardrops, eye ointments, powders and solutions are
also contemplated as being within the scope of this invention.
[0127] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0128] Powders and sprays can contain, in addition to the compounds
of this invention, lactose, talc, silicic acid, aluminum hydroxide,
calcium silicates and polyamide powder, or mixtures of these
substances. Sprays can additionally contain customary propellants
such as chlorofluorohydrocarbons.
[0129] Compounds of the invention can also be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes may
be used. The present compositions in liposome form may contain, in
addition to the compounds of the invention, stabilizers,
preservatives, and the like. The preferred lipids are the natural
and synthetic phospholipids and phosphatidylcholines (lecithins)
used separately or together.
[0130] Methods to form liposomes are known in the art. See, for
example, Prescott, Ed., Methods in Cell Biology, Volume XIV,
Academic Press, New York, N.Y., (1976), p 33 et seq.
[0131] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants. Ophthalmic formulations, eye ointments,
powders and solutions are also contemplated as being within the
scope of this invention. Aqueous liquid compositions of the
invention also are particularly useful.
[0132] The compounds of the invention can be used in the form of
pharmaceutically acceptable salts derived from inorganic or organic
acids.
[0133] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides such as methyl,
ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl
sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates;
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides; arylalkyl halides such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0134] Examples of acids which can be employed to form
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric
acid and phosphoric acid and such organic acids as benzenesulfonic
acid, citric acid, gluconic acid, maleic acid, oxalic acid, and
succinic acid.
[0135] Basic addition salts can be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on
alkali metals or alkaline earth metals such as lithium, sodium,
potassium, calcium, magnesium, and aluminum salts, and the like,
and nontoxic quaternary ammonia and amine cations including
ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, diethylamine,
ethylamine and the like. Other representative organic amines useful
for the formation of base addition salts include ethylenediamine,
ethanolamine, diethanolamine, piperidine, and piperazine.
[0136] Compounds of the invention may exist as prodrugs. Prodrugs
of the invention can be rapidly transformed in vivo to a parent
compound of the invention, for example, by hydrolysis in blood. A
thorough discussion is provided in T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium
Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug
Design, American Pharmaceutical Association and Pergamon Press
(1987).
[0137] The invention also contemplates pharmaceutically acceptable
compounds that when administered to a patient in need thereof may
be converted through in vivo biotransformation into compounds of
formula (I).
Methods of the Invention
[0138] Compounds and compositions of the invention are useful for
modulating the effects of NNRs, and more particularly .alpha.7
NNRs, .alpha.4.beta.2 NNRs, or both .alpha.7 and .alpha.4.beta.2
NNRs. In particular, the compounds and compositions of the
invention can be used for treating or preventing disorders
modulated by .alpha.7 NNRs, or .alpha.4.beta.2 NNRs, or both
.alpha.7 and .alpha.4.beta.2 NNRs. Typically, such disorders can be
ameliorated by selectively modulating the .alpha.7 NNRs,
.alpha.4.beta.2 NNRs, or both .alpha.7 and .alpha.4.beta.2 NNRs in
a mammal, preferably by administering a compound or composition of
the invention, either alone or in combination with one or more
additional pharmaceutical agents, for example, as part of a
therapeutic regimen.
[0139] Compounds for the method of the invention, including but not
limited to those specified in the examples or otherwise
specifically named, can modulate, and often possess an affinity
for, NNRs, and more particularly .alpha.7 NNRs, .alpha.4.beta.2
NNRs, or both .alpha.7 and .alpha.4.beta.2 NNRs. As .alpha.7 NNRs,
.alpha.4.beta.2 NNRs, or both .alpha.7 and .alpha.4.beta.2 NNRs
ligands, the compounds of the invention can be useful for the
treatment or prevention of a number of .alpha.7 NNR,
.alpha.4.beta.2 NNR, or both .alpha.7 and .alpha.4.beta.2 NNR
mediated diseases or conditions.
[0140] Specific examples of compounds that can be useful for the
treatment or prevention of .alpha.7, .alpha.4.beta.2, or both
.alpha.7 and .alpha.4.beta.2 NNRs mediated diseases or conditions
include, but are not limited to, compounds described in the
Compounds of the Invention and also in the Examples.
[0141] Methods for preparing compounds useful in the method of the
invention also can be found in Iriepa, I, et al. J. Molec. Struct.
1999, 509, 105; Flynn, D. L., et al. Bioorganic & Medicinal
Chemistry Letters, 1992, 2, 1613; U.S. Pat. No. 4,816,453; WO
94/00454; U.S. Pat. No. 5,280,028; U.S. Pat. No. 5,399,562; WO
92/15593; U.S. Pat. No. 5,260,303; U.S. Pat. No. 5,591,749; U.S.
Pat. No. 5,434,151; and U.S. Pat. No. 5,604,239.
[0142] For example, .alpha.7 NNRs have been shown to play a
significant role in enhancing cognitive function, including aspects
of learning, memory and attention (Levin, E. D., J. Neurobiol. 53:
633-640, 2002). As such, .alpha.7 ligands are suitable for the
treatment of conditions and disorders related to memory and/or
cognition including, for example, attention deficit disorder, ADHD,
AD, mild cognitive impairment, senile dementia, AIDS dementia,
Pick's disease, dementia associated with Lewy bodies, and dementia
associated with Down's syndrome, as well as CDS.
[0143] In addition, .alpha.7-containing NNRs have been shown to be
involved in the cytoprotective effects of nicotine both in vitro
(Jonnala, R. B. and Buccafusco, J. J., J. Neurosci. Res. 66:
565-572, 2001) and in vivo (Shimohama, S. et al., Brain Res. 779:
359-363, 1998). More particularly, neurodegeneration underlies
several progressive CNS disorders, including, but not limited to,
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, dementia with Lewy bodies, as well
as diminished CNS function resulting from traumatic brain injury.
For example, the impaired function of .alpha.7 NNRs by
.beta.-amyloid peptides linked to Alzheimer's disease has been
implicated as a key factor in development of the cognitive deficits
associated with the disease (Liu, Q.-S., Kawai, H., Berg, D. K.,
Proc. Natl. Acad. Sci. USA 98: 4734-4739, 2001). .alpha.7 selective
ligands can influence neuroprotective pathways leading to decreased
phosphorylation of the tau protein, whose hyperphosphorylation is
required for neurofibrillary tangle formation in various tau
related pathologies such as Alzheimer's disease and various other
dementias (Bitner et al., Soc. Neuroscience, 2006 abst 325.6). The
activation of .alpha.7 NNRs has been shown to block this
neurotoxicity (Kihara, T. et al., J. Biol. Chem. 276: 13541-13546,
2001). As such, selective ligands that enhance .alpha.7 activity
can counter the deficits of Alzheimer's and other neurodegenerative
diseases.
[0144] .alpha.7 NNRs also have been implicated in aspects of
neurodevelopment, for example neurogenesis of the brain (Falk, L.
et al., Developmental Brain Research 142:151-160, 2003; Tsuneki,
H., et al., J. Physiol. (London) 547:169-179, 2003; Adams, C. E.,
et al., Developmental Brain Research 139:175-187, 2002). As such,
.alpha.7 NNRs can be useful in preventing or treating conditions or
disorders associated with impaired neurodevelopment, for example
schizophrenia. (Sawa A., Mol. Med. 9:3-9, 2003).
[0145] Several compounds with high affinity for .alpha.4.beta.2
NNRs have been shown to improve attentive and cognitive performance
in preclinical models that are relevant to
attention-deficit/hyperactivity disorder (ADHD), a disease
characterized by core symptoms of hyperactivity, inattentiveness,
and impulsivity. For example, ABT-418, a full agonist at
.alpha.4.beta.2 NNRs, is efficacious in a variety of preclinical
cognition models. ABT-418 administered transdermally, was shown in
a controlled clinical trial in 32 adults to be effective in
treating ADHD in general, and attentional/cognitive deficits in
particular (Wilens, T. E.; Biederman, J.; Spencer, T. J.; Bostic,
J.; Prince, J.; Monuteaux, M. C.; Soriano, J.; Fince, C.; Abrams,
A.; Rater, M.; Polisner, D., The American Journal of Psychiatry
(1999)156(12), 1931-1937). Likewise, ABT-418 showed a signal of
efficacy in a pilot Alzheimer's disease trial. ABT-089, a
.alpha.4.beta.2 selective partial agonist, has been shown in rodent
and primate animal models to improve attention, learning, and
memory deficits. ABT-089 and another .alpha.4.beta.2 agonist,
ispronicline have shown efficacy in a pilot clinical trials
(Wilens, T. E.; Verlinden, M. H.; Adler, L. A.; Wozniak, P. J.;
West, S. A. Biological Psychiatry (2006), 59(11), 1065-1070.
Geerts, H., Curr. Opin. Invest. Drugs (2006), 7(1), 60-69). In
addition to cognition, compounds that interact with .alpha.4.beta.2
NNRs such as ABT-594 and others are also efficacious in preclinical
and clinical models of pain. As such, ligands that modulate both
.alpha.7 and .alpha.4.beta.2 activity can have broader spectrum of
therapeutic efficacy in disease states such as those involving
cognitive and attentive deficits, pain, neurodegenerative diseases
and others.
[0146] Schizophrenia is a complex disease that is characterized by
abnormalities in perception, cognition, and emotions. Significant
evidence implicates the involvement of .alpha.7 NNRs in this
disease, including a measured deficit of these receptors in
post-mortem patients (Sawa A., Mol. Med. 9:3-9, 2003; Leonard, S.
Eur. J. Pharmacol. 393: 237-242, 2000). Deficits in sensory
processing (gating) are one of the hallmarks of schizophrenia.
These deficits can be normalized by nicotinic ligands that operate
at the .alpha.7 NNR (Adler L. E. et al., Schizophrenia Bull. 24:
189-202, 1998; Stevens, K. E. et al., Psychopharmacology 136:
320-327, 1998). More recent studies have shown that .alpha.4.beta.2
nicotinic receptor stimulation also contributes to the effects of
nicotine in the DBA/2 mouse model of sensory gating (Radek et al.,
Psychopharmacology (Berl). 2006 187:47-55). Thus, .alpha.7 and
.alpha.7/.alpha.4.beta.2 ligands demonstrate potential in the
treatment schizophrenia.
[0147] A population of .alpha.7 or .alpha.4.beta.2 NNRs in the
spinal cord modulate neurotransmission that has been associated
with the pain-relieving effects of nicotinic compounds
(Cordero-Erausquin, M. and Changeux, J.-P., Proc. Natl. Acad. Sci.
USA 98:2803-2807, 2001). The .alpha.7 NNR or and
.alpha.7/.alpha.4.beta.2 ligands demonstrate therapeutic potential
for the treatment of pain states, including acute pain,
post-surgical pain, as well as chronic pain states including
inflammatory pain and neuropathic pain.
[0148] Compounds of the invention are particularly useful for
treating and preventing a condition or disorder affecting memory,
cognition, neurodegeneration, neurodevelopment, and
schizophrenia.
[0149] Cognitive impairment associated with schizophrenia (CDS)
often limits the ability of patients to function normally, a
symptom not adequately treated by commonly available treatments,
for example, treatment with an atypical antipsychotic. (Rowley, M.
et al., J. Med. Chem. 44: 477-501, 2001). Such cognitive deficit
has been linked to dysfunction of the nicotinic cholinergic system,
in particular with decreased activity at .alpha.7 receptors.
(Friedman, J. I. et al., Biol. Psychiatry, 51: 349-357, 2002).
Thus, activators of .alpha.7 receptors can provide useful treatment
for enhancing cognitive function in schizophrenic patients who are
being treated with atypical antipsychotics. Accordingly, the
combination of an .alpha.7 NNR ligand and one or more atypical
antipsychotic would offer improved therapeutic utility. Specific
examples of suitable atypical antipsychotics include, but are not
limited to, clozapine, risperidone, olanzapine, quietapine,
ziprasidone, zotepine, iloperidone, and the like.
[0150] Compounds of the invention may be administered alone or in
combination (i.e. co-administered) with one or more additional
pharmaceutical agents. Combination therapy includes administration
of a single pharmaceutical dosage formulation containing one or
more of the compounds of invention and one or more additional
pharmaceutical agents, as well as administration of the compounds
of the invention and each additional pharmaceutical agent, in its
own separate pharmaceutical dosage formulation. For example, a
compound of formula (I) and one or more additional pharmaceutical
agents, may be administered to the patient together, in a single
oral dosage composition having a fixed ratio of each active
ingredient, such as a tablet or capsule; or each agent may be
administered in separate oral dosage formulations.
[0151] Where separate dosage formulations are used, compounds of
the invention and one or more additional pharmaceutical agents may
be administered at essentially the same time (e.g., concurrently)
or at separately staggered times (e.g., sequentially).
[0152] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention can be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0153] When used in the above or other treatments, a
therapeutically effective amount of one of the compounds of the
invention can be employed in pure form or, where such forms exist,
in pharmaceutically acceptable salts thereof. Compounds of the
invention can also be administered as a pharmaceutical composition
containing the compound of interest in combination with one or more
pharmaceutically acceptable carriers. The phrase "therapeutically
effective amount" of the compound of the invention means a
sufficient amount of the compound to treat disorders, at a
reasonable benefit/risk ratio applicable to any medical treatment.
It will be understood, however, that the total daily usage of the
compounds and compositions of the invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; activity
of the specific compound employed; the specific composition
employed; the age, body weight, general health, sex and diet of the
patient; the time of administration, route of administration, and
rate of excretion of the specific compound employed; the duration
of the treatment; drugs used in combination or coincidental with
the specific compound employed; and like factors well-known in the
medical arts. For example, it is well within the skill of the art
to start doses of the compound at levels lower than required to
achieve the desired therapeutic effect and to gradually increase
the dosage until the desired effect is achieved.
[0154] The total daily dose of the compounds of this invention
administered to a human or lower animal range from about 0.10
.mu.g/kg body weight to about 10 mg/kg body weight. More preferable
doses can be in the range of from about 0.10 .mu.g/kg body weight
to about 1 mg/kg body weight. If desired, the effective daily dose
can be divided into multiple doses for purposes of administration.
Consequently, single dose compositions may contain such amounts or
submultiples thereof to make up the daily dose.
Methods for Preparing Compounds of the Invention
[0155] This invention is intended to encompass compounds of the
invention when prepared by synthetic processes or by metabolic
processes. Preparation of the compounds of the invention by
metabolic processes include those occurring in the human or animal
body (in vivo) or processes occurring in vitro.
[0156] The synthesis of compounds of formula (I) wherein the groups
R.sup.X, R.sup.Y, R.sup.Z, and A have the meanings as set forth in
the Summary of the Invention section unless otherwise noted, is
exemplified in Schemes 4 and 5.
[0157] As used in the descriptions of the schemes and the examples,
certain abbreviations are intended to have the following meanings:
BOC for tert-butoxycarbonyl; BSS for balanced salt solution; HPLC
for high pressure liquid chromatography; and Tris for
tris(hydroxymethyl)aminomethane.
[0158] Compounds of general formula (I) can be prepared from
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one using general procedures
as outlined in Scheme 4.
##STR00007##
[0159] Hydroxyamine ethers of formula (1), can be treated with
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (prepared as reported in
Becker, D. P. and Flynn, D. L. Synthesis 1992, 1080-1082), to
provide oxime ethers of formula (2). Conversion of
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one to compounds of formula
(4) can be achieved by reaction with hydrazides of formula (3).
Both reactions are generally conducted under acidic conditions
wherein the acid is added prior to the reaction or is present as an
acid salt of (1) or (3), at a temperature range from about room
temperature to about 80.degree. C., in a solvent such as
ethanol.
[0160] 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one can also be
treated with amines of formula (4a), hydrazines of formula (4c) and
semicarbazides of formula (4e) to provide compounds of formula
(4b), (4d) and (4f) respectively, using procedures similar to those
known in the literatures. Many of the amines of formula (4a) and
hydrazines of formula (4c) are commercially available.
Semicarbazides of formula (4e) can be prepared from isocyanates or
hydrazines using procedures analogous to those described in J. Med.
Chem. (2003) 46, 1493-1503.
[0161] Hydroxyamine ethers of formula (1) can be prepared using
general procedures as illustrated in Scheme 5.
##STR00008##
[0162] Boronic acids of formula (5) when treated with
N-hydroxyphthalimide utilizing conditions known to those skilled in
the art, for example, via a copper mediated cross-coupling reaction
conditions, provide compounds of formula (6). For example, boronic
acids of formula (5) and hydroxyphthalimide in the presence of a
copper salt and a base and in a solvent such as but not limited to
dichloromethane or 1,2-dichloroethane or mixtures thereof,
optionally in the presence of molecular sieves, can be converted to
compounds of formula (6). The reaction is generally carried out at
temperature ranging from about room temperature to about
150.degree. C. Examples of copper salts include, but are not
limited, to Cu(CO.sub.2CH.sub.3).sub.2, CuCl, and
CuBr.S(CH.sub.3).sub.2. Examples of bases include, but are not
limited to pyridine, 4-dimethylaminopyridine, and
triethylamine.
[0163] Treatment of (6) with hydrazine monohydrate in solvents such
as but not limited to chloroform, methanol or mixtures thereof
provides hydroxyamine ethers (1).
[0164] Alternatively, hydroxyamine ethers of formula (1) can be
obtained from alcohols of formula (7) as described in Chem.
Commun., 2000, 975-976, by treatment with a base followed by
tert-butyl 2-(trichloromethyl)-1,2-oxaziridine-3-carboxylate.
Examples of suitable bases for such conversion include, but are not
limited to, sodium hydride, n-butyllithium, and the like. The
reaction is generally carried out below ambient temperature and in
a solvent such as, but not limited to, ether, tetrahydrofuran, or
mixtures thereof.
[0165] Hydrazides of formula (3) can be prepared using
methodologies analogous to those known in the art. For example, by
acylating acid chlorides of formula AC(O)Cl (prepared from the
corresponding acids) with appropriate hydrazines of formula
NH(R.sup.X)NH.sub.2.
[0166] It will be appreciated that the synthetic schemes and
specific examples as illustrated in the synthetic examples section
are illustrative and are not to be read as limiting the scope of
the invention as it is defined in the appended claims. All
alternatives, modifications, and equivalents of the synthetic
methods and specific examples are included within the scope of the
claims.
[0167] Optimum reaction conditions and reaction times for each
individual step may vary depending on the particular reactants
employed and substituents present in the reactants used. Unless
otherwise specified, solvents, temperatures and other reaction
conditions may be readily selected by one of ordinary skill in the
art. Specific procedures are provided in the Synthetic Examples
section. Reactions may be worked up in the convention manner, e.g.
by eliminating the solvent from the residue and further purified
according to methodologies generally known in the art such as, but
not limited to, crystallization, distillation, extraction,
trituration and chromatography. Unless otherwise described, the
starting materials and reagents are either commercially available
or may be prepared by one skilled in the art from commercially
available materials using methods described in the chemical
literature.
[0168] Routine experimentations, including appropriate manipulation
of the reaction conditions, reagents and sequence of the synthetic
route, protection of any chemical functionality that may not be
compatible with the reaction conditions, and deprotection at
suitable point in the reaction sequence of the method are included
in the scope of the invention. Suitable protecting groups and the
methods for protecting and deprotecting different substituents
using such suitable protecting groups are well known to those
skilled in the art; examples of which may be found in T. Greene and
P. Wuts, Protecting Groups in Chemical Synthesis (3.sup.rd ed.),
John Wiley & Sons, NY (1999), which is incorporated herein by
reference in its entirety. Synthesis of the compounds of the
invention may be accomplished by methods analogous to those
described in the synthetic schemes described hereinabove and in
specific examples.
[0169] Starting materials, if not commercially available, may be
prepared by procedures selected from standard organic chemical
techniques, techniques that are analogous to the synthesis of
known, structurally similar compounds, or techniques that are
analogous to the above described schemes or the procedures
described in the synthetic examples section.
[0170] When an optically active form of a compound of the invention
is required, it may be obtained by carrying out one of the
procedures described herein using an optically active starting
material (prepared, for example, by asymmetric induction of a
suitable reaction step), or by resolution of a mixture of the
stereoisomers of the compound or intermediates using a standard
procedure (such as chromatographic separation, recrystallization or
enzymatic resolution).
[0171] Similarly, when a pure geometric isomer of a compound of the
invention is required, it may be obtained by carrying out one of
the above procedures using a pure geometric isomer as a starting
material, or by resolution of a mixture of the geometric isomers of
the compound or intermediates using a standard procedure such as
chromatographic separation.
[0172] The compounds of the invention and processes for making
compounds for the method of the invention will be better understood
by reference to the following examples, which are intended as an
illustration of and not a limitation upon the scope of the
invention.
EXAMPLES
Example 1
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-2-naphthyloxime
Example 1A
2-(2-naphthyloxy)-1H-isoindole-1,3(2H)-dione
[0173] The title compound was prepared as described in Example 3A,
substituting 2-naphthylboronic acid for 4-chlorophenyboronic
acid.
Example 1B
O-(2-naphthyl)hydroxylamine
[0174] The title compound was prepared as described in Example 3B,
substituting Example 1A for Example 3A. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.16 (dd, J=9, 3 Hz, 1H), 7.24-7.31 (m, 1H),
7.35-7.42 (m, 1H), 7.55 (d, J=2 Hz, 1H), 7.67-7.76 (m, 3H); MS
(DCl/NH.sub.3) m/z 160 (M+H).
Example 1C
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-2-naphthyloxime
[0175] 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (74 mg, 0.49 mmol)
(prepared as reported in: Becker, D. P. and Flynn, D. L. Synthesis
1992, 1080-1082) and Example 1B (78 mg, 0.48 mmol) were combined in
a test tube. Ethanol (4 mL) was added, followed by concentrated HCl
(0.1 mL). The mixture was heated to boiling for 30 seconds, and the
resulting solution was allowed to cool to room temperature
overnight. The mixture was concentrated under vacuum, and the
residue was crystallized from ethanol (1 mL) and ethyl acetate (5
mL) to provide the title compound as a hydrochloride salt. .sup.1H
NMR (300 MHz, CD.sub.3OD) .delta. 2.18 (t, J=13 Hz, 2H), 2.34-2.49
(m, 3H), 3.10-3.16 (m, 1H), 3.65-3.76 (m, 4H), 3.77-3.84 (m, 1H),
3.83-3.90 (m, 1H), 4.10 (s, 1H), 7.30-7.36 (m, 2H), 7.40-7.48 (m,
1H), 7.64 (d, J=2 Hz, 1H), 7.73-7.85 ppm (m, 3H); MS (DCl/NH.sub.3)
m/z 293 (M+H).sup.+.
Example 2
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(pentafluorobenzyl)oxime
[0176] Solid O-(perfluorobenzyl)hydroxylamine HCl (167 mg, 0.669
mmol, Aldrich Chemical Co.) was added to a warm solution of
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (102 mg, 0.675 mmol)
(prepared as reported in: Becker, D. P. and Flynn, D. L. Synthesis
1992, 1080-1082) in ethanol (1 mL). The mixture was swirled with
warming to dissolve all solids. The nearly colorless solution was
allowed to cool to room temperature overnight. The solvent was
removed under vacuum, and the residue was crystallized from 10%
ethanol in ethyl acetate (3 mL) to provide the title compound as
hydrochloride salt. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.87-2.06 (m, 2H), 2.22 (q, J=3 Hz, 1H), 2.24-2.37 (m, 2H), 2.83
(s, 1H), 3.30, (m, 1H), 3.43-3.57 (m, 2H), 3.64 (s, 2H), 3.66-3.78
(m, 2H), 5.15-5.24 ppm (m, 2H); MS (DCl/NH.sub.3) m/z 347
(M+H).sup.+; Anal. C.sub.16H.sub.15N.sub.2OF.sub.5--HCl requires C,
50.21; H, 4.21; N, 7.32. Found C, 50.20; H, 3.99; N, 7.22.
Example 3
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(4-chlorophenyl)oxime
Example 3A
N-(4-Chlorophenoxy)phthalimide
[0177] Pyridine (0.37 mL, 4.6 mmol) was added to a suspension of
N-hydroxyphthalimide (664 mg, 4.1 mmol), 4-chlorophenylboronic acid
(635 mg, 4.1 mmol), and powdered 4 .ANG. molecular sieves (1.02 g)
in CH.sub.2Cl.sub.2 (20 mL). Cupric acetate monohydratc (812 mg,
4.1 mmol) was added, and the mixture was stirred open to the
atmosphere at room temperature for 18 hours. Silica gel (10 g) was
added, and the slurry was concentrated to dryness under vacuum. The
residue was applied to the top of a flash chromatography column,
and eluted with hexanes:ethyl acetate (80:20) to provide the title
compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.11-7.17 (m,
2H), 7.27-7.34 (m, 2H), 7.79-7.87 (m, 2H), 7.88-7.95 ppm (m,
2H).
Example 3B
O-(4-chlorophenyl)hydroxylamine
[0178] Hydrazine hydrate (0.56 mL, 12 mmol) was added to a solution
of Example 3A (820 mg, 3.0 mmol) in chloroform (37 mL) and methanol
(4 mL). The suspension was stirred at room temperature for 22
hours. Silica gel (10 g) was added, and the mixture was
concentrated to dryness. The residue was applied to the top of a
flash chromatography column and eluted with hexanes-ethyl acetate
(80:20) to provide the title compound as the free amine. The
residue was dissolved in ethanol (5 mL) and treated with
HCl/dioxane (4 M, 1 mL). The solution was heated at reflux and
diluted with gradual addition of ethyl acetate (50 mL). The mixture
was cooled to room temperature and filtered to provide the title
compound as a hydrochloride salt. .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.15-7.22 (m, 2H), 7.42-7.49 (m, 2H).
Example 3C
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(4-chlorophenyl)oxime
[0179] Example 3B (63 mg, 0.35 mmol) was added to a warm solution
of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (53 mg, 0.35 mmol)
(prepared as reported in: Becker, D. P. and Flynn, D. L. Synthesis
1992, 1080-1082) in ethanol (2 mL). The mixture swirled with
warming to dissolve all solids. The solution was allowed to stand
at room temperature overnight, and crystallization was initiated by
scratching with a glass rod. The resulting suspension was heated to
dissolve the solids, and allowed to cool gradually to 0.degree. C.
to complete precipitation. The resulting solid was isolated by
filtration and recrystallized from ethanol (1 mL) to provide the
title compound as a hydrochloride salt. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 2.13 (t, J=13 Hz, 2H), 2.30-2.47 (m, 3H), 3.06
(s, 1H), 3.57-3.87 (m, 6H), 4.00 (s, 1H), 7.12-7.21 (m, 2H),
7.25-7.34 ppm (m, 2H); MS (DCl/NH.sub.3) m/z 277/279 (M+H).sup.+;
Anal. C.sub.15H.sub.17N.sub.2OCl HCl requires C, 57.52; H, 5.79; N,
8.94. Found C, 57.24; H, 5.82; N, 8.62.
Example 4
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(6-chloropyridin-3-yl)oxime
Example 4A
2-[(6-chloropyridin-3-yl)oxy]-1H-isoindole-1,3(2H)-dione
[0180] The title compound was prepared as described in Example 3A,
substituting 6-chloropyridin-3-ylboronic acid for
4-chlorophenyboronic acid.
Example 4B
O-(6-chloropyridin-3-yl)hydroxylamine
[0181] The title compound was prepared as described in Example 3B,
substituting Example 4A for Example 3A. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.22 (d, J=8 Hz, 1H), 7.48 (dd, J=9, 3 Hz, 1H),
8.26 ppm (d, J=3 Hz, 1H).
Example 4C
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one
O-(6-chloropyridin-3-yl)oxime
[0182] A solution of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (120
mg, 0.80 mmol) (prepared as reported in: Becker, D. P. and Flynn,
D. L. Synthesis 1992, 1080-1082) in ethanol (3.6 mL) was added to
Example 4B (152 mg, 0.84 mmol). Concentrated HCl (12 M, 0.2 mL) was
added, and the solution was heated at reflux for 5 minutes, and
allowed to stand at room temperature for 60 hours. The solution was
concentrated under vacuum and the residue was purified by
chromatography (silica gel, eluted with
CH.sub.2Cl.sub.2--CH.sub.3OH--NH.sub.4OH, 90:10:1). The free amine
(70 mg) was dissolved in warm ethyl acetate (3 mL) and a solution
of p-toluenesulfonic acid monohydrate (46 mg, 024 mmol) in warm
ethyl acetate (1 mL) was added. The solution was heated to reflux,
then allowed to cool gradually to -10.degree. C. and kept at that
temperature overnight. The solid was collected by filtration and
dried under vacuum to provide the title compound as a
p-toluenesulfonate salt: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
2.07-2.21 (m, 2H), 2.33-2.47 (m, 3H), 2.36 (s, 3H), 3.05-3.10 (m,
1H), 3.62-3.74 (m, 4H), 3.75-3.88 (m, 2H), 4.01 (s, 1H), 7.23 (d,
J=8 Hz, 2H), 7.41 (d, J=9 Hz, 1H), 7.65-7.73 (m, 3H), 8.29 ppm (d,
J=3 Hz, 1H); MS (DCl/NH.sub.3) m/z 278/280 (M+H).sup.+.
Example 5
N'-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylidene-1H-indole-3-carbohydrazide
Example 5A
1H-Indole-3-carboxylic acid hydrazide
[0183] Indole-3-carboxylic acid (500 mg, 3.1 mmol) was stirred at
room temperature with thionyl chloride (5 mL, 68 mmol) for 20
hours. The solution was concentrated under vacuum and the residue
was taken up in ether (10 mL) and concentrated to dryness (repeated
three times) to ensure removal of the thionyl chloride. The
resulting solid was dissolved in ether (5 mL) and added to an ice
cooled solution of hydrazine hydrate (600 mg, 12 mmol) in
tetrahydrofuran (5 mL). After 30 minutes, the solid was collected
by filtration, washed with 5% NaOH and water, and dried under
vacuum at 50.degree. C. The crude hydrazide was recrystallized from
95% ethanol to provide the title compound. .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.11-7.22 (m, 2H), 7.42 (dd, J=7, 2 Hz, 1H),
7.83 (s, 1H), 8.02-8.08 ppm (m, 1H); MS (DCl/NH.sub.3) m/z 176
(M+H).sup.+.
Example 5B
N'-1-azatricyclo[3.3.1.1.sup.3,7]dec-4-ylidene-1H-indole-3-carbohydrazide
[0184] A mixture of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (65
mg, 0.43 mmol) (prepared as reported in Becker, D. P. and Flynn, D.
L. Synthesis 1992, 1080-1082) and Example 5A (80 mg, 0.46 mmol)
were combined in a test tube with ethanol (7 mL). Concentrated
hydrochloric acid (12 M, 0.04 mL) was added, and the mixture was
heated at reflux until the solids dissolved. The solution was
allowed to stand at room temperature overnight, then concentrated
under vacuum. The residue was triturated with 10% ethanol in ethyl
acetate (7 mL) and filtered to provide the title compound as the
hydrochloride salt. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 1.94
(d, J=13 Hz, 2H), 2.08 (br. s, 3H), 2.26 (d, J=12 Hz, 2H),
3.38-3.58 (m, 4H), 3.69 (d, J=12 Hz, 2H), 7.16-7.28 (m, 2H), 7.46
(dd, J=6, 1 Hz, 1H), 7.93-7.98 (d, J=3 Hz, 1H), 8.09 ppm (dd, J=6,
2 Hz, 1H); MS (DCl/NH.sub.3) m/z 309 (M+H).sup.+.
Example 6
1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one O-benzyloxime
[0185] A mixture of 1-azatricyclo[3.3.1.1.sup.3,7]decan-4-one (45
mg, 0.30 mmol) (prepared as reported in Becker, D. P. and Flynn, D.
L. Synthesis 1992, 1080-1082) and O-benzylhydroxylaminc
hydrochloride (Aldrich, 51 mg, 0.32 mmol) were combined in a test
tube with ethanol (3 mL). Concentrated hydrochloric acid (12 M, 0.1
mL) was added, and the mixture was heated at reflux until the
solids dissolved. The solution was allowed to stand at room
temperature overnight, then concentrated under vacuum. The residue
was dissolved in acetonitrile (0.7 mL), and the solution was
diluted with ethyl acetate (5 mL). The resulting white precipitate
was collected by filtration, washed with ethyl acetate (2 mL) and
dried under vacuum to provide the title compound as the
hydrochloride salt. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.89-2.07 (m, 2H), 2.15-2.37 (m, 3H), 2.85 (s, 1H), 3.42-3.85 (m,
7H), 5.08 (s, 2H), 7.24-7.40 ppm (m, 5H); MS (DCl/NH.sub.3) m/z 257
(M+H).sup.+; Anal. C.sub.16H.sub.20N.sub.2O-2HCl requires C, 58.36;
H, 6.73; N, 8.51. Found C, 58.61; H, 6.49; N, 8.48.
Determination of Biological Activity
[0186] To determine the effectiveness of representative compounds
of this invention as ligands for .alpha.7 NNRs, the compounds of
the invention were evaluated according to the [.sup.3H]-DPPB
binding assay. To determine the effectiveness of representative
compounds of this invention as ligands for .alpha.4.beta.2 NNRs,
the compounds of the invention were evaluated according to the
[.sup.3H]-cytisine binding assay, which were performed as described
below.
[.sup.3H]-Cytisine Binding
[0187] Binding to .alpha.4.beta.2 NNRs subtype was determined
according to the conditions which were modified from the procedures
described in Pabreza L. A., Dhawan, S., Kellar K. J.,
[.sup.3H]-Cytisine Binding to Nicotinic Cholinergic Receptors in
Brain, Mol. Pharm. 39: 9-12, 1991. Membrane enriched fractions from
rat brain minus cerebellum (ABS Inc., Wilmington, Del.) were slowly
thawed at 4.degree. C., washed and resuspended in 30 volumes of
BSS-Tris buffer (120 mM NaCl/5 mM KCl/2 mM CaCl.sub.2/2 mM
MgCl.sub.2/50 mM Tris-Cl, pH 7.4, 4.degree. C.). Samples containing
100-200 .mu.g of protein and 0.75 nM [.sup.3H]-cytisine (30
C.sub.i/mmol; Perkin Elmer/NEN Life Science Products, Boston,
Mass.) were incubated in a final volume of 500 .mu.L for 75 minutes
at 4.degree. C. Seven log-dilution concentrations of each compound
were tested in duplicate. Non-specific binding was determined in
the presence of 10 .mu.M (-)-nicotine. Bound radioactivity was
isolated by vacuum filtration onto prewetted glass fiber filter
plates (Millipore, Bedford, Mass.) using a 96-well filtration
apparatus (Packard Instruments, Meriden, Conn.) and were then
rapidly rinsed with 2 mL of ice-cold BSS buffer (120 mM NaCl/5 mM
KCl/2 mM CaCl.sub.2/2 mM MgCl.sub.2). Packard MicroScint-20.RTM.
scintillation cocktail (40 .mu.L) was added to each well and
radioactivity determined using a Packard TopCount.RTM. instrument.
The IC.sub.50 values were determined by nonlinear regression in
Microsoft Excel.RTM. software. K.sub.i values were calculated from
the IC.sub.50s using the Cheng-Prusoff equation, where
K.sub.i=IC.sub.50/(1+[Ligand]/K.sub.D).
[.sup.3H]-DPPB Binding
[0188] [.sup.3H]-DPPB,
[.sup.3H]-(S,S)-2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide, binding to the .alpha.7 NNR subtype
was determined using membrane enriched fractions from rat brain
minus cerebellum or human cortex (ABS Inc., Wilmington, Del.) as
described in Anderson, D. J.; Bunnelle, W.; Surber, B.; Du, J.;
Surowy, C.; Tribollet, E.; Margucrat, A.; Bertrand, D.;
Gopalakrishnan, M. J. Pharmacol. Exp. Ther. (2008), 324, 179-187
which is incorporated herein by reference. Briefly, pellets were
thawed at 4.degree. C., washed and resuspended with a Polytron at a
setting of 7 in 30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM
KCl, 2 mM CaCl.sub.2, 2 mM MgCl.sub.2, and 50 mM Tris-Cl, pH 7.4,
4.degree. C.). Seven log-dilution concentrations of test compounds
containing 100-200 .mu.g of protein, and 0.5 nM [.sup.3H]-DPPB
(62.8 Ci/mmol; R46V, Abbott Labs) were incubated in a final volume
of 500 .mu.L for 75 minutes at 4.degree. C. in duplicate.
Non-specific binding was determined in the presence of 10 .mu.M
methyllycaconitine. Bound radioactivity was collected on Millipore
MultiScreen.RTM. harvest plates FB presoaked with 0.3%
polyethyleneimine using a Packard cell harvester, washed with 2.5
mL ice-cold buffer, and radioactivity was determined using a
Packard TopCount Microplate beta counter. IC.sub.50 values were
determined by nonlinear regression in Microsoft.RTM. Excel or Assay
Explorer. K.sub.i values were calculated from the IC.sub.50s using
the Cheng-Prusoff equation, where
K.sub.i=IC.sub.50/(1+[Ligand]/K.sub.D). [.sup.3H]-DPPB was obtained
according to the preparation procedures described below.
[Methyl-.sup.3H]2,2-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide Preparation
[0189]
[Methyl-.sup.3H]2,2-dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-az-
onia-bicyclo[2.2.1]heptane; iodide used in the [.sup.3H]-DPPB
binding assay above was prepared according to the following
procedures.
Step 1: Preparation of t-Butyl
(S,S)-5-(6-Phenyl-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbo-
xylate
[0190] Triethylamine (20 mL) was added to a suspension of t-butyl
(S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.43 g, 17.3
mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine
(3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL)
and the mixture was heated under nitrogen at 100.degree. C. for 7
days. The dark mixture was cooled to room temperature, and the
resulting precipitate was isolated by filtration, washed with
toluene (15 mL) and dried under vacuum to provide the title
compound. The filtrate was concentrated and the residue was
purified by column chromatography on silica gel, eluting with ethyl
acetate, to provide additional product: MS (DCl/NH.sub.3) m/z 353
(M+H).sup.+.
Step 2: Preparation of (S,S)-2-Methyl
5-(6-phenyl-pyridazin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane
[0191] The product obtained from Step 1 (3.41 g, 9.7 mmol) was
dissolved in formic acid (20 mL) and treated with formalin (37% by
weight, 1.0 g, 12.3 mmol). The mixture was heated at 100.degree. C.
for 1 hour, and the brown solution was cooled to room temperature
and concentrated under vacuum. The residue was purified by column
chromatography on silica gel, eluting with
CH.sub.2Cl.sub.2--CH.sub.3OH--NH.sub.4OH (95:5:1) to provide the
title compound: MS (DCl/NH.sub.3) m/z 267 (M+H).sup.+.
Step 3: Preparation of
[.sup.3H]-(S,S)-2,2-Dimethyl-5-(6-phenyl-pyridazin-3-yl)-5-aza-2-azonia-b-
icyclo[2.2.1]heptane iodide ([.sup.3H]-DPPB)
[0192] [.sup.3H]Methyl iodide in toluene (250 mCi in 0.1 mL,
85Ci/mmol, American Radiolabeled Chemicals, Inc.) was combined with
a solution of the product obtained from Step 2 in dichloromethane
(0.788 mg, 2.96 .mu.mole in 0.45 mL). The vial was capped and the
mixture was allowed to react overnight at room temperature.
Methanol was added and the solvents were evaporated to give 42 mCi.
The product was taken up in methanol for HPLC purification.
Step 4: Purification by High Performance Liquid Chromatography
(HPLC)
[0193] About 7 mCi of [.sup.3H]-DPPB was evaporated to dryness and
the residue was dissolved in total about 4.5 mL
acetonitrile:water:trifluoroacetic acid (15:85:0.1). Approximately
0.9 mL per injection were made onto a Phenomenex.RTM. Luna.RTM.
C18(2) column (5 micron, 250 mm.times.4.6 mm ID) using an Agilent
HPLC system. [.sup.3H]-DPPB was eluted by a gradient mobile phase
from 10% B to 20% B in 20 minutes where Mobile Phase A=0.1%
trifluoroacetic acid in water and Mobile Phase B=0.1%
trifluoroacetic acid in acetonitrile at a flow rate of
approximately 1 mL/minute. Peak detection and chromatograms were
obtained with an Agilent variable wavelength UV detector set at 275
nm. The fractions containing [.sup.3H]-DPPB were collected at
approximately 14 minutes using an Agilent fraction collector. The
fractions were combined and the solvents were evaporated in vacuo.
The residue was dissolved in 200 proof ethanol (2 mL) to give 0.7
mCi.
Step 5: Determination of Purity and Specific Activity
[0194] [.sup.3H]-DPPB was assayed using an Agilent 1100 series HPLC
system consisting of a quaternary pump, an autosampler, and a
photodiode array UV detector. A Packard Radiomatic A 500
radioactivity detector was connected to the HPLC system. For
radiodetection, a 500 .mu.L flow cell and a 3:1 ratio of Ultima-Flo
M scintillation cocktail to HPLC mobile phase were used. The
analyses were performed using a Phenomenex.RTM. Luna.RTM. C18(2)
column (5 microns, 250 mm.times.4.6 mm ID). The mobile phase
consisted of a gradient starting with 10% B and ramping to 20% B in
20 minutes followed by ramping to 90% B in 1 minute and hold at 90%
B for 9 minutes, where Mobile Phase A=0.1% trifluoroacetic acid in
water and Mobile Phase B=0.1% trifluoroacetic acid in acetonitrile.
The flow rate was set at approximately 1 mL/minute and the UV
detection was set at 275 nm.
[0195] Compounds of the invention typically exhibited binding
values (K.sub.i) below 10 micromolar in one or both of these assays
([.sup.3H]-Cytisine or [.sup.3H]-DPPB binding). Preferred compounds
had Ki values ranging from 0.01 nanomolar to 100 nanomolar in one
or both binding assays.
[0196] Compounds of the invention are ligands at .alpha.4.beta.2,
.alpha.7 NNRs, or both .alpha.4.beta.2 and .alpha.7 NNRs that
modulate function of .alpha.4.beta.2, .alpha.7 NNRs, or both
.alpha.4.beta.2 and .alpha.7 NNRs by altering the activity of the
receptor or signaling. The compounds can be inverse agonists that
inhibit the basal activity of the receptor or antagonists that
completely block the action of receptor-activating agonists. The
compounds also can be partial agonists that partially block or
partially activate the .alpha.4.beta.2, .alpha.7, or both
.alpha.4.beta.2 and .alpha.7 NNR receptor or agonists that activate
the receptor. Binding to .alpha.4.beta.2, .alpha.7, or both
.alpha.4.beta.2 and .alpha.7 receptors also trigger key signaling
processes involving various kinases and phosphatases and
protein-protein interactions that are important to effects on
memory, cytoprotection, gene transcription and disease
modification.
[0197] Compounds of the invention can exist in radiolabeled form
containing one or more atoms having an atomic mass or mass number
different from the atomic mass or mass number most abundantly found
in nature. Radioisotopes of atoms such as hydrogen, carbon,
phosphorous, sulfur, fluorine, chlorine, and iodine include, but
are not limited to, .sup.3H, .sup.14C, .sup.32P, .sup.35S,
.sup.18F, .sup.36Cl, and .sup.125I, respectively. Compounds that
contain other radioisotopes of these and/or other atoms are within
the scope of this invention. Compounds containing tritium (.sup.3H)
and .sup.14C radioisotopes are preferred in general for their ease
in preparation and detectability. Radiolabeled compounds of this
invention can be prepared by the general methods well known to
persons having ordinary skill in the art. Such radiolabeled
compounds can be conveniently prepared by carrying out the
procedures disclosed in the above Examples and Schemes by
substituting a readily available radiolabeled reagent for a
non-radiolabeled reagent. The radiolabeled compounds of the
invention can be used as standards to determine the effectiveness
of .alpha.7 NNR ligands in binding assays such as the assays
described above.
[0198] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
* * * * *