U.S. patent application number 11/106778 was filed with the patent office on 2005-08-11 for pharmaceutical composition for the treatment of cns and other disorders.
This patent application is currently assigned to Pfizer Inc. Invention is credited to Coe, Jotham Wadsworth, O'Donnell, Christopher J., O'Neill, Brian Thomas.
Application Number | 20050176720 11/106778 |
Document ID | / |
Family ID | 22981913 |
Filed Date | 2005-08-11 |
United States Patent
Application |
20050176720 |
Kind Code |
A1 |
O'Neill, Brian Thomas ; et
al. |
August 11, 2005 |
Pharmaceutical composition for the treatment of CNS and other
disorders
Abstract
The present invention relates to a method of treating disorders
of the Central Nervous System (CNS) and other disorders in a
mammal, including a human, by administering to the mammal a
CNS-penetrant .alpha.7 nicotinic receptor agonist. It also relates
to pharmaceutical compositions containing a pharmaceutically
acceptable carrier and a CNS-penetrant .alpha.7 nicotinic receptor
agonist.
Inventors: |
O'Neill, Brian Thomas; (Old
Saybrook, CT) ; Coe, Jotham Wadsworth; (Niantic,
CT) ; O'Donnell, Christopher J.; (Mystic,
CT) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Assignee: |
Pfizer Inc
|
Family ID: |
22981913 |
Appl. No.: |
11/106778 |
Filed: |
April 15, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11106778 |
Apr 15, 2005 |
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10833714 |
Apr 27, 2004 |
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6881734 |
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10833714 |
Apr 27, 2004 |
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10229447 |
Aug 28, 2002 |
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6809094 |
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10229447 |
Aug 28, 2002 |
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10047850 |
Oct 23, 2001 |
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60258736 |
Dec 29, 2000 |
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Current U.S.
Class: |
514/249 ;
544/351 |
Current CPC
Class: |
A61P 25/14 20180101;
A61P 9/08 20180101; A61P 25/24 20180101; A61P 25/28 20180101; A61P
25/00 20180101; A61P 25/20 20180101; A61P 25/18 20180101; A61P
25/34 20180101; A61P 1/04 20180101; C07D 471/08 20130101; A61P
25/16 20180101; A61P 25/22 20180101; A61P 21/02 20180101; A61P 9/12
20180101; A61P 3/04 20180101; A61P 25/04 20180101; A61P 9/10
20180101; A61P 25/30 20180101; A61P 25/32 20180101; A61P 25/06
20180101; A61P 9/06 20180101; A61P 25/10 20180101; A61P 25/36
20180101 |
Class at
Publication: |
514/249 ;
544/351 |
International
Class: |
A61K 031/498 |
Claims
1-13. (canceled)
14. A compound of the formula 6wherein n=2; m=2; o=1; A=O, S or
NR.sup.1; B=N or CR.sup.2; Q=N or CR.sup.3; D=N or CR.sup.4; E=N or
CR.sup.5; R.sup.1 is H, a straight chain or branched
(C.sub.1-C.sub.8)alkyl, C(.dbd.O)OR.sup.6, CH.sub.2R.sup.6,
C(.dbd.O)NR.sup.6R.sup.7, C(.dbd.O)R.sup.6, or SO.sub.2R.sup.6;
each R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is independently
selected from F, Cl, Br, I, nitro, cyano, CF.sub.3,
--NR.sup.6R.sup.7, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)R.sup.7R.sup.8, --NR.sup.6C(.dbd.O)OR.sup.7,
--NR.sup.6S(.dbd.O).sub.2R.sup.7,
--NR.sup.6S(.dbd.O).sub.2NR.sup.7R.sup.- 8, --OR.sup.6,
--OC(.dbd.O)R.sup.6, --OC(.dbd.O)OR.sup.6,
--OC(.dbd.O)NR.sup.6R.sup.7, --OC(.dbd.O)SR.sup.6,
--C(.dbd.O)OR.sup.6, --C(.dbd.O)R.sup.6,
--C(.dbd.O)NR.sup.6R.sup.7, --SR.sup.6, --S(.dbd.O)R.sup.6,
--S(.dbd.O).sub.2R.sup.6, --S(.dbd.O).sub.2NR.sup.6R.- sup.7, and
R.sup.6; each R.sup.6, R.sup.7, and R.sup.8 is independently
selected from H, straight chain or branched (C.sub.1-C.sub.8)alkyl,
straight chain or branched (C.sub.2-C.sub.8)alkenyl, straight chain
or branched (C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.4-C.sub.8)cycloalkenyl, 3-8 membered heterocycloalkyl groups
selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,
tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,
thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
3H-indolyl, quinuclidinyl and quinolizinyl,
(C.sub.5-C.sub.11)bicycloalkyl, (C.sub.7-C.sub.11)bicycloalkenyl,
5-11 membered heterobicycloalkyl groups consisting of non-aromatic
two-ringed cyclic groups, wherein at least one of the rings
contains a heteroatom selected from O, S, or N, 5-11 membered
heterobicycloalkenyl groups consisting of non-aromatic two-ringed
cyclic groups, wherein at least one of the rings-contains a
heteroatom selected from O, S, or N and at least one endocyclic or
exocyclic double bond, (C.sub.6-C.sub.11)aryl, and 5-12 membered
heteroaryls selected from pyridinyl, pyridazinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,
tetrahydroisoquinolyl, benzofuryl, furopyridinyl,
pyrolopyrimidinyl, and azaindolyl; wherein each R.sup.6, R.sup.7,
and R.sup.8 is optionally substituted with from one to six
substituents, independently selected from F, Cl, Br, I, nitro,
cyano, CF.sub.3, --NR.sup.9R.sup.10, --NR.sup.9C(.dbd.O)R.sup.10,
--NR.sup.9C(.dbd.O)NR.sup.10R.sup.11, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9S(.dbd.O).sub.2R.sup.10,
--NR.sup.9S(.dbd.O).sub.2NR.sup.10R.sup.11, --OR.sup.9,
--OC(.dbd.O)R.sup.9, --OC(.dbd.O)OR.sup.9,
--OC(.dbd.O)NR.sup.9R.sup.10, --OC(.dbd.O)SR.sup.9,
--C(.dbd.O)OR.sup.9, --C(.dbd.O)R.sup.9,
--C(.dbd.O)NR.sup.9R.sup.10, --SR.sup.9, --S(.dbd.O)R.sup.9,
--S(.dbd.O).sub.2R.sup.9, --S(.dbd.O).sub.2NR.sup.9R.sup.10 and
R.sup.9; each R.sup.9, R.sup.10 and R.sup.11 is independently
selected from H, straight chain or branched (C.sub.1-C.sub.8)alkyl,
straight chain or branched (C.sub.2-C.sub.8)alkenyl, straight chain
or branched (C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.4-C.sub.8)cycloalkenyl, 3-8 membered heterocycloalkyl groups
selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,
tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,
thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
3H-indolyl, quinuclidinyl and quinolizinyl,
(C.sub.5-C.sub.11)bicycloalkyl, (C.sub.7-C.sub.11)bicycloalkenyl,
5-11 membered heterobicycloalkyl groups consisting of non-aromatic
two-ringed cyclic groups, wherein at least one of the rings
contains a heteroatom selected from O, S, or N, 5-11 membered
heterobicycloalkenyl groups consisting of non-aromatic two-ringed
cyclic groups, wherein at least one of the rings contains a
heteroatom selected from O, S, or N and at least one endocyclic or
exocyclic double bond, (C.sub.6-C.sub.11) aryl or 5-12 membered
heteroaryls selected from pyridinyl, pyridazinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
dihydroquinolyl, tetrahydroquinolyl dihydroisoquinolyl,
tetrahydroisoquinolyl, benzofuryl, furopyridinyl,
pyrolopyrimidinyl, and azaindolyl; wherein each R.sup.9, R.sup.10
and R.sup.11 is optionally substituted with from one to six
substituents independently selected from F, Cl, Br, I, nitro,
cyano, CF.sub.3, --NR.sup.12R.sup.13, --NR.sup.12C(.dbd.O)R.sup.13,
--NR.sup.12C(.dbd.O)NR.sup.13R.sup.14,
--NR.sup.12C(.dbd.)OR.sup.13, --NR.sup.12S(.dbd.O).sub.2R.sup.13,
--NR.sup.12S(.dbd.O).sub.2NR.sup.13R.sup.14, --OR.sup.12,
--OC(.dbd.O)R.sup.12, --OC(.dbd.O)OR.sup.2,
--OC(.dbd.O)NR.sup.12R.sup.13- , --OC(.dbd.O)SR.sup.12,
--C(.dbd.O)OR.sup.12, --C(.dbd.O)R.sup.12,
--C(.dbd.O)NR.sup.12R.sup.13, --SR.sup.12, S(.dbd.O)R.sup.12,
--S(.dbd.O).sub.2R.sup.12, --S(.dbd.O).sub.2NR.sup.12R.sup.13 and
R.sup.12; each R.sup.12, R.sup.13, and R.sup.14 is independently
selected from H, straight chain or branched (C.sub.1-C.sub.8)alkyl,
straight chain or branched (C.sub.2-C.sub.8)alkenyl, straight chain
or branched (C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.4-C.sub.8)cycloalkenyl, 3-8 membered heterocycloalkyl groups
selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,
azepinyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl,
oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl,
tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,
thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl,
dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
3H-indolyl, quinuclidinyl and quinolizinyl,
(C.sub.5-C.sub.11)bicycloalkyl, (C.sub.7-C.sub.11)bicycloalkenyl,
5-11 membered heterobicycloalkyl groups consisting of non-aromatic
two-ringed cyclic groups, wherein at least one of the rings
contains a heteroatom selected from O, S, or N, 5-11 membered
heterobicycloalkenyl groups consisting of non-aromatic two-ringed
cyclic groups, wherein at least one of the rings contains a
heteroatom selected from O, S, or N and at least one endocyclic or
exocyclic double bond, (C.sub.6-C.sub.11) aryl and 5-12 membered
heteroaryls selected from pyridinyl, pyridazinyl, imidazolyl,
pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,
tetrahydroisoquinolyl, benzofuryl, furopyridinyl,
pyrolopyrimidinyl, and azaindolyl; or R.sup.2 and R.sup.3, or
R.sup.3 and R.sup.4, or R.sup.4 and R.sup.5, may form another
6-membered aromatic or heteroaromatic ring sharing B and Q, or Q
and D, or D and E, respectively, and may be optionally substituted
with from one to four substituents independently selected from the
group of radicals set forth in the definition of R.sup.6, R.sup.7
and R.sup.8 above; or an enantiomeric, diastereomeric, or
tautomeric isomer thereof, or a pharmaceutically acceptable salt of
such compound or isomer.
15. A compound according to claim 14 wherein A=S.
16. A compound according to claim 14 wherein A=O.
17. A compound according to claim 16 wherein B=CR.sup.2,
Q=CR.sup.3, D=CR.sup.4, E=CR.sup.5.
18. A compound according to claim 16 wherein B=N, Q=CR.sup.3,
D=CR.sup.4, and, E=CR.sup.5.
19. A compound according to claim 16 wherein B=CR.sup.2, Q=N,
D=CR.sup.4, and E=CR.sup.5.
20. A compound according to claim 16 wherein B=CR.sup.2,
Q=CR.sup.3, D=N and E=CR.sup.5.
21. A compound according to claim 16 wherein B=CR.sup.2,
Q=CR.sup.3, D=CR.sup.4 and E=N.
22. A pharmaceutical composition for the treatment of schizophrenia
in a mammal, comprising an amount of a compound according to claim
14 that is effective in treating schizophrenia and a
pharmaceutically acceptable carrier.
23. A method of treating schizophrenia in a mammal, comprising
administering to said mammal an amount of a compound according to
claim 14 that is effective in treating schizophrenia.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to a method of treating
disorders of the Central Nervous System (CNS) and other disorders
in a mammal, including a human, by administering to the mammal a
CNS-penetrant .alpha.7 nicotinic receptor agonist. It also relates
to pharmaceutical compositions containing a pharmaceutically
acceptable carrier and a CNS-penetrant .alpha.7 nicotinic receptor
agonist.
[0002] Schizophrenia is characterized by some or all of the
following symptoms: delusions (i.e., thoughts of grandeur,
persecution, or control by an outside force), auditory
hallucinations, incoherence of thought, loss of association between
ideas, marked poverty of speech, and loss of emotional
responsiveness. Schizophrenia has long been recognized as a complex
disease, which to date has eluded biochemical or genetic
characterization. However, recent data in the literature suggest
that .alpha.7 nicotinic receptor agonists may be therapeutic for
this, and other CNS disorders, see: Alder, L. E.; Hoffer, L. D.;
Wiser, A.; Freedman, R. Am. J. Psychiatry 1993, 150, 1856;
Bickford, P. C.; Luntz-Leybman, V.; Freedman, R. Brain Research,
1993, 607, 33; Stevens, K. E.; Meltzer, J.; Rose, G. M.
Psychopharmacology 1995, 119, 163; Freedman, R.; Coon, H.;
Myles-Worsley, M.; Orr-Urtreger, A.; Olincy, A.; Davis, A.;
Polymeropoulos, M.; Holik, J.; Hopkins, J.; Hoff, M.; Rosenthal,
J.; Waldo, M. C.; Reimherr, F.; Wender, P.; Yaw, J.; Young, D. A.;
Breese, C. R.; Adams, C.; Patterson, D.; Alder, L. E.; Kruglyak,
L.; Leonard, S.; Byerley, W. Proc. Nat. Acad., Sci. USA 1997, 94,
587.
[0003] The compositions of the present invention that contain an
.alpha.7 nicotinic receptor agonist are useful for the treatment of
depression. As used herein, the term "depression" includes
depressive disorders, for example, single episodic or recurrent
major depressive disorders, and dysthymic disorders, depressive
neurosis, and neurotic depression; melancholic depression including
anorexia, weight loss, insomnia and early morning waking, and
psychomotor retardation; atypical depression (or reactive
depression) including increased appetite, hypersomnia, psychomotor
agitation or irritability, anxiety and phobias, seasonal affective
disorder, or bipolar disorders or manic depression, for example,
bipolar I disorder, bipolar II disorder and cyclothymic
disorder.
[0004] Other mood disorders encompassed within the term
"depression" include dysthymic disorder with early or late onset
and with or without atypical features; dementia of the Alzheimer's
type, with early or late onset, with depressed mood; vascular
dementia with depressed mood, mood disorders induced by alcohol,
amphetamines, cocaine, hallucinogens, inhalants, opioids,
phencyclidine, sedatives, hypnotics, anxiolytics and other
substances; schizoaffective disorder of the depressed type; and
adjustment disorder with depressed mood.
[0005] The compositions of the present invention that contain an
.alpha.7 nicotinic receptor agonist are useful for the treatment of
anxiety. As used herein, the term "anxiety" includes anxiety
disorders, such as panic disorder with or without agoraphobia,
agoraphobia without history of panic disorder, specific phobias,
for example, specific animal phobias, social phobias,
obsessive-compulsive disorder, stress disorders including
post-traumatic stress disorder and acute stress disorder, and
generalized anxiety disorders.
[0006] "Generalized anxiety" is typically defined as an extended
period (e.g. at least six months) of excessive anxiety or worry
with symptoms on most days of that period. The anxiety and worry is
difficult to control and may be accompanied by restlessness, being
easily fatigued, difficulty concentrating, irritability, muscle
tension, and disturbed sleep.
[0007] "Panic disorder" is defined as the presence of recurrent
panic attacks followed by at least one month of persistent concern
about having another panic attack. A "panic attack" is a discrete
period in which there is a sudden onset of intense apprehension,
fearfulness or terror. During a panic attack, the individual may
experience a variety of symptoms including palpitations, sweating,
trembling, shortness of breath, chest pain, nausea and dizziness.
Panic disorder may occur with or without agoraphobia.
[0008] "Phobias" includes agoraphobia, specific phobias and social
phobias. "Agoraphobia" is characterized by an anxiety about being
in places or situations from which escape might be difficult or
embarrassing or in which help may not be available in the event of
a panic attack. Agoraphobia may occur without history of a panic
attack. A "specific phobia" is characterized by clinically
significant anxiety provoked by feared object or situation.
Specific phobias include the following subtypes: animal type, cued
by animals or insects; natural environment type, cued by objects in
the natural environment, for example storms, heights or water,
blood-injection-injury type, cued by the sight of blood or an
injury or by seeing or receiving an injection or other invasive
medical procedure; situational type, cued by a specific situation
such as public transportation, tunnels, bridges, elevators, flying,
driving or enclosed spaces; and other type where fear is cued by
other stimuli. Specific phobias may also be referred to as simple
phobias. A "social phobia" is characterized by clinically
significant anxiety provoked by exposure to certain types of social
or performance circumstances. Social phobia may also be referred to
as social anxiety disorder.
[0009] Other anxiety disorders encompassed within the term
"anxiety" include anxiety disorders induced by alcohol,
amphetamines, caffeine, cannabis, cocaine, hallucinogens,
inhalants, phencychdine, sedatives, hypnotics, anxiolytics and
other substances, and adjustment disorders with anxiety or with
mixed anxiety and depression.
[0010] Anxiety may be present with or without other disorders such
as depression in mixed anxiety and depressive disorders. The
compositions of the present invention are therefore useful in the
treatment of anxiety with or without accompanying depression.
[0011] By the use of a CNS-penetrant .alpha.7 nicotinic receptor
agonist in accordance with the present invention, it is possible to
treat depression and/or anxiety in patients for whom conventional
antidepressant or antianxiety therapy might not be wholly
successful or where dependence upon the antidepressant or
antianxiety therapy is prevalent.
SUMMARY OF THE INVENTION
[0012] This invention relates to compounds of the formula I 1
[0013] wherein n=1-2;
[0014] m=1-2;
[0015] o=1-2;
[0016] A=O, S or NR.sup.1;
[0017] B=N or CR.sup.2;
[0018] Q=N or CR.sup.3;
[0019] D=N or CR.sup.4;
[0020] E=N or CR.sup.5;
[0021] R.sup.1 is H, a straight chain or branched
(C.sub.1-C.sub.9)alkyl, C(.dbd.O)OR.sup.6, CH.sub.2R.sup.6,
C(.dbd.O)NR.sup.6R.sup.7, C(.dbd.O)R.sup.6, or SO.sub.2R.sup.6;
[0022] each R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is independently
selected from F, Cl, Br, I, nitro, cyano, CF.sub.3,
--NR.sup.6R.sup.7, --NR.sup.6C(.dbd.O)R.sup.7,
--NR.sup.6C(.dbd.O)NR.sup.7R.sup.8, --NR.sup.6C(.dbd.O)OR.sup.7,
--NR.sup.6S(.dbd.O).sub.2R.sup.7,
--NR.sup.6S(.dbd.O).sub.2NR.sup.7R.sup.8, --OR.sup.6,
--OC(.dbd.O)R.sup.6, --OC(.dbd.O)OR.sup.6,
--OC(.dbd.O)NR.sup.6R.sup.7, --OC(.dbd.O)SR.sup.6,
--C(.dbd.O)OR.sup.6, --C(.dbd.O)R.sup.6,
--C(.dbd.O)NR.sup.6R.sup.7, --SR.sup.6, --S(.dbd.O)R.sup.6,
--S(.dbd.O).sub.2R.sup.6, --S(.dbd.O).sub.2NR.sup.6R.sup.7, and
R.sup.6;
[0023] each R.sup.6, R.sup.7, and R.sup.8 is independently selected
from H, straight chain or branched (C.sub.1-C.sub.8) alkyl,
straight chain or branched (C.sub.2-C.sub.8)alkenyl, straight chain
or branched (C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.4-C.sub.8)cycloalkenyl, 3-8 membered heterocycloalkyl,
(C.sub.5-C.sub.11)bicycloalkyl, (C.sub.7-C.sub.11)bicycloalkenyl,
5-11 membered heterobicycloalkyl, 5-11 membered
heterobicycloalkenyl, (C.sub.6-C.sub.11) aryl, and 5-12 membered
heteroaryl; wherein each R.sup.6, R.sup.7, and R.sup.8 is
optionally substituted with from one to six substituents,
independently selected from F, Cl, Br, I, nitro, cyano, CF.sub.3,
--NR.sup.9R.sup.10, --NR.sup.9C(.dbd.O)R.sup.10,
--NR.sup.9C(.dbd.O)NR.sup.10R.sup.11, --NR.sup.9C(.dbd.O)OR.sup.10,
--NR.sup.9S(.dbd.O).sub.2R.sup.10,
--NR.sup.9S(.dbd.O).sub.2NR.sup.11R.su- p.11, --OR.sup.9,
--OC(.dbd.O)R.sup.9, --OC(.dbd.O)OR.sup.9,
--OC(.dbd.O)NR.sup.9R.sup.10, --OC(.dbd.O)SR.sup.9,
--C(.dbd.O)OR.sup.9, --C(.dbd.O)R.sup.9,
--C(.dbd.O)NR.sup.9R.sup.10, --SR.sup.9, --S(.dbd.O)R.sup.9,
--S(.dbd.O).sub.2R.sup.9, --S(.dbd.O).sub.2NR.sup.9R.- sup.10 and
R.sup.9;
[0024] each R.sup.9, R.sup.10 and R.sup.11 is independently
selected from H, straight chain or branched (C.sub.1-C.sub.8)alkyl,
straight chain or branched (C.sub.2-C.sub.8)alkenyl, straight chain
or branched (C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.4-C.sub.8)cycloalkenyl, 3-8 membered heterocycloalkyl,
(C.sub.5-C.sub.11)bicycloalkyl, (C.sub.7-C.sub.11)bicycloalkenyl,
5-11 membered heterobicycloalkyl, (5-11
membered)heterobicycloalkenyl, (C.sub.6-C.sub.11)aryl or 5-12
membered heteroaryl; wherein each R.sup.9, R.sup.10 and R.sup.11 is
optionally substituted with from one to six substituents
independently selected from F, Cl, Br, I, nitro, cyano, CF.sub.3,
--NR.sup.12R.sup.13, --NR.sup.12C(.dbd.O)R.sup.13,
--NR.sup.12C(.dbd.O)NR.sup.13R.sup.14,
--NR.sup.12C(.dbd.O)OR.sup.13, --NR.sup.12S(.dbd.O).sub.2R.sup.13,
--NR.sup.12S(.dbd.O).sub.2NR.sup.13R.- sup.14, --OR.sup.12,
--OC(.dbd.O)OR.sup.12, --OC(.dbd.O)NR.sup.12R.sup.13,
--OC(.dbd.O)SR.sup.12, --C(.dbd.O)OR.sup.12, --C(.dbd.O)R.sup.12,
--C(.dbd.O)NR.sup.12R.sup.13, --SR.sup.12, --S(.dbd.O)R.sup.12,
--S(.dbd.O).sub.2R.sup.12, --S(.dbd.O).sub.2NR.sup.12R.sup.13 and
R.sup.12;
[0025] each R.sup.12, R.sup.13, and R.sup.14 is independently
selected from H, straight chain or branched (C.sub.1-C.sub.8)alkyl,
straight chain or branched (C.sub.2-C.sub.8)alkenyl, straight chain
or branched (C.sub.2-C.sub.8)alkynyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.4-C.sub.8)cycloalkenyl, 3-8 membered heterocycloalkyl,
(C.sub.5-C.sub.11)bicycloalkyl, (C.sub.7-C.sub.11)bicycloalkenyl,
5-11 membered heterobicycloalkyl, 5-11 membered
heterobicycloalkenyl, (C.sub.6-C.sub.11)aryl and (5-12
membered)heteroaryl;
[0026] or R.sup.2 and R.sup.3, or R.sup.3 and R.sup.4, or R.sup.4
and R.sup.5, may form another 6-membered aromatic or heteroaromatic
ring sharing B and Q, or Q and D, or D and E, respectively, and may
be optionally substituted with from one to four substituents
independently selected from the group of radicals set forth in the
definition of R.sup.6, R.sup.7 and R.sup.8 above;
[0027] and all enantiomeric, diastereomeric, and tautomeric isomers
and pharmaceutically acceptable salts thereof.
[0028] More specific embodiments of this invention relate to
compounds of the formula I wherein n=1, m=2, and o=1.
[0029] More specific embodiments of this invention relate to
compounds of the formula I wherein A=S.
[0030] More specific embodiments of this invention relate to
compounds of the formula I wherein A=NR.sup.1.
[0031] More specific embodiments of this invention relate to
compounds of the formula I wherein A=O.
[0032] More specific embodiments of this invention relate to
compounds of the formula I wherein A=O, B=CR.sup.2, Q=CR.sup.3,
D=CR.sup.4, E=CR.sup.5.
[0033] More specific embodiments of this invention relate to
compounds of the formula I wherein A=O, B=N, Q=CR.sup.3,
D=CR.sup.4, E=CR.sup.5.
[0034] More specific embodiments of this invention relate to
compounds of the formula I wherein A=O, B=CR.sup.2, Q=N,
D=CR.sup.4, E=CR.sup.5.
[0035] More specific embodiments of this invention relate to
compounds of the formula I wherein A=O, B=CR.sup.2, Q=CR.sup.3,
D=N, E=CR.sup.5.
[0036] More specific embodiments of this invention relate to
compounds of the formula I wherein A=O, B=CR.sup.2, Q=CR.sup.3,
D=CR.sup.4, E=N.
[0037] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight or branched moieties. Examples of alkyl groups
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
and t-butyl.
[0038] The term "alkenyl", as used herein, unless otherwise
indicated, includes alkyl moieties having at least one
carbon-carbon double bond wherein alkyl is as defined above.
Examples of alkenyl include, but are not limited to, ethenyl and
propenyl.
[0039] The term "alkynyl", as used herein, unless otherwise
indicated, includes alkyl moieties having at least one
carbon-carbon triple bond wherein alkyl is as defined above.
Examples of alkynyl groups include, but are not limited to, ethynyl
and 2-propynyl.
[0040] The term "cycloalkyl", as used herein, unless otherwise
indicated, includes non-aromatic saturated cyclic alkyl moieties
wherein alkyl is as defined above. Examples of cycloalkyl include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and cycloheptyl. "Bicycloalkyl" groups are non-aromatic
saturated carbocyclic groups consisting of two rings. Examples of
bicycloalkyl groups include, but are not limited to,
bicyclo-[2.2.2]-octyl and norbornyl. The term "cycloalkenyl" and
"bicycloalkenyl" refer to non-aromatic carbocyclic cycloalkyl and
bicycloalkyl moieties as defined above, except comprising of one or
more carbon-carbon double bonds connecting carbon ring members (an
"endocyclic" double bond) and/or one or more carbon-carbon double
bonds connecting a carbon ring member and an adjacent non-ring
carbon (an "exocyclic" double bond). Examples of cycloalkenyl
groups include, but are not limited to, cyclopentenyl and
cyclohexenyl. A non-limiting example of a bicycloalkenyl group is
norborenyl. Cycloalkyl, cycloalkenyl, bicycloalkyl, and
bicycloalkenyl groups also include groups similar to those
described above for each of these respective categories, but which
are substituted with one or more oxo moieties. Examples of such
groups with oxo moieties include, but are not limited to
oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl, and
norcamphoryl.
[0041] The term "aryl", as used herein, unless otherwise indicated,
includes an organic radical derived from an aromatic hydrocarbon by
removal of one hydrogen atom. Examples of aryl groups include, but
are not limited to phenyl and naphthyl.
[0042] The terms "heterocyclic" and "heterocycloalkyl", as used
herein, refer to non-aromatic cyclic groups containing one or more
heteroatoms, preferably from one to four heteroatoms, each selected
from O, S and N. "Heterobicycloalkyl" groups are non-aromatic
two-ringed cyclic groups, wherein at least one of the rings
contains a heteroatom (O, S, or N). The heterocyclic groups of this
invention can also include ring systems substituted with one or
more oxo moieties. Examples of non-aromatic heterocyclic groups
include, but are not limited to, aziridinyl, azetidinyl,
pyrrolidinyl, piperidinyl, azepinyl, piperazinyl,
1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl,
piperidino, morpholino, thiomorpholino, thioxanyl, pyrrolinyl,
indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,
pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,
pyrazolidinyl, imidazolinyl, imidazolidinyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
3H-indolyl, quinuclidinyl and quinolizinyl.
[0043] The term "heteroaryl", as used herein, refers to aromatic
groups containing one or more heteroatoms (O, S, or N). A
multicyclic group containing one or more heteroatoms wherein at
least one ring of the group is aromatic is a heteroaryl group. The
heteroaryl groups of this invention can also include ring systems
substituted with one or more oxo moieties. Examples of heteroaryl
groups include, but are not limited to, pyridinyl, pyridazinyl,
imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl,
isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,
oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,
indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,
purinyl, oxadiazolyl, thiazolyl, thiadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl,
benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl,
dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl,
tetrahydroisoquinolyl, benzofuryl, furopyridinyl,
pyrolopyrimidinyl, and azaindolyl.
[0044] The foregoing heteroaryl, heterocyclic and heterocycloalkyl
groups may be C-attached or N-attached (where such is possible).
For instance, a group derived from pyrrole may be pyrrol-1-yl
(N-attached) or pyrrol-3-yl (C-attached).
[0045] Examples of specific compounds of this invention are the
following compounds of the formula I and their pharmaceutically
acceptable salts, hydrates, solvates and optical and other
stereoisomers:
[0046] 4-Benzooxazol-2-yl-1,4-diaza-bicyclo[3.2.2]nonane;
[0047]
2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-1-oxa-3-aza-cyclopenta[b]-naph-
thalene;
[0048] 4-Benzothiazol-2-yl-1,4-diaza-bicyclo[3.2.2]nonane;
[0049]
4-(5-Phenyl-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0050]
4-(1H-Benzoimidazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0051]
4-(6-Phenyl-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0052]
2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-oxa-1-aza-cyclopenta[a]-naph-
thalene;
[0053]
4-(5-Chloro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0054]
4-(5-Fluoro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0055]
4-(6-Nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0056]
4-Oxazolo[5,4-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane;
[0057]
4-Oxazolo[5,4-c]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane;
[0058]
4-Oxazolo[4,5-c]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane;
[0059]
4-Oxazolo[4,5-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane;
[0060]
4-(5-Pyridin-3-yl-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]-nonane-
;
[0061]
4-(5-Bromo-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0062]
4-(6-Bromo-oxazolo[5,4-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]-non-
ane;
[0063]
4-(5-Iodo-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0064]
4-(4-Nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0065]
4-(5-Nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0066]
4-(5-Methyl-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0067]
4-(6-Methyl-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0068]
4-(5-Methyl-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]non-
ane;
[0069]
4-(6-Chloro-5-nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonan-
e;
[0070]
4-(5-Chloro-6-nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonan-
e;
[0071]
Benzyl-[2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzooxazol-5-yl]-amin-
e;
[0072]
[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzooxazol-5-yl]-(3-phenyl-a-
llyl)-amine;
[2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-benzooxazol-5-yl]-pyrid-
in-3-ylmethyl-amine;
[0073]
Dibenzyl-[2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzooxazol-5-yl]-am-
ine;
[0074]
4-(5-m-Tolyl-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane;
[0075]
4-(6-Phenyl-oxazolo[5,4-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]non-
ane;
[0076]
4-[5-(4-Trifluoromethyl-phenyl)-benzooxazol-2-yl]-1,4-diaza-bicyclo-
[3.2.2]nonane;
[0077]
4-(6-Bromo-oxazolo[4,5b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonan-
e;
[0078]
4-(6-Phenyl-oxazolo[4,5-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]non-
ane; and
[0079]
4-(5,7-Dichloro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane.
[0080] Unless otherwise indicated, the term "one or more
substituents", as used herein, refers to from one to the maximum
number of substituents possible based on the number of available
bonding sites.
[0081] The term "treatment", as used herein, refers to reversing,
alleviating, inhibiting the progress of, or preventing the disorder
or condition to which such term applies, or one or more symptoms of
such condition or disorder. The term "treatment", as used herein,
refers to the act of treating, as "treating" is defined immediately
above.
[0082] Compounds of formula I may contain chiral centers and
therefore may exist in different enantiomeric and diastereomeric
forms. Individual isomers can be obtained by known methods, such as
optical resolution, optically selective reaction, or
chromatographic separation in the preparation of the final product
or its intermediate. This invention relates to all optical isomers
and all stereoisomers of compounds of the formula I, both as
racemic mixtures and as individual enantiomers and diastereoismers
of such compounds, and mixtures thereof, and to all pharmaceutical
compositions and methods of treatment defined above that contain or
employ them, respectively.
[0083] In so far as the compounds of formula I of this invention
are basic compounds, they are all capable of forming a wide variety
of different salts with various inorganic and organic acids.
Although such salts must be pharmaceutically acceptable for
administration to animals, it is often desirable in practice to
initially isolate the base compound from the reaction mixture as a
pharmaceutically unacceptable salt and then simply convert to the
free base compound by treatment with an alkaline reagent and
thereafter convert the free base to a pharmaceutically acceptable
acid addition salt. The add addition salts of the base compounds of
this invention are readily prepared by treating the base compound
with a substantially equivalent amount of the chosen mineral or
organic acid in an aqueous solvent or in a suitable organic
solvent, such as methanol or ethanol. Upon careful evaporation of
the solvent, the desired solid salt is readily obtained. The acids
which are used to prepare the pharmaceutically acceptable add
addition salts of the aforementioned base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmaceutically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or
bisulfate, phosphate or acid phosphate, acetate, lactate, citrate
or acid citrate, tartrate or bi-tartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate
(i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate))salts.
[0084] The present invention also includes isotopically labelled
compounds, which are identical to those recited in formula I, but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the present invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
sulfur, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.11C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
Compounds of the present invention, prodrugs thereof, and
pharmaceutically acceptable salts of said compounds or of said
prodrugs which contain the aforementioned isotopes and/or other
isotopes of other atoms are within the scope of this invention.
Certain isotopically labelled compounds of the present invention,
for example those into which radioactive isotopes such as .sup.3H
and .sup.14C are incorporated, are useful in drug and/or substrate
tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labelled compounds of formula I of this
invention and prodrugs thereof can generally be prepared by
carrying out the procedures disclosed in the Schemes and/or in the
Examples and Preparations below, by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
[0085] The present invention also relates to a pharmaceutical
composition for the treatment of schizophrenia in a mammal,
including a human, comprising an amount of a compound of the
formula I, or a pharmaceutically acceptable salt thereof, that is
effective in treating schizophrenia and a pharmaceutically
acceptable carrier.
[0086] The present invention also relates to a method of treating
schizophrenia in a mammal, including a human, comprising
administering to said mammal an amount of a compound of the formula
I, or a pharmaceutically acceptable salt thereof, that is effective
in treating schizophrenia.
[0087] The present invention also relates to a pharmaceutical
composition for the treatment of schizophrenia in a mammal,
including a human, comprising an .alpha.7 nicotinic receptor
agonist compound of the formula I, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
[0088] The present invention also relates to a method of treating
schizophrenia in a mammal, including a human, comprising
administering to said mammal an .alpha.7 nicotinic receptor
agonizing amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof.
[0089] The present invention also relates to a pharmaceutical
composition for treating a disorder or condition selected from
inflammatory bowel disease (including but not limited to ulcerative
colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel
syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue,
pouchitis vasoconstriction, anxiety, panic disorder, depression,
bipolar disorder, autism, sleep disorders; jet lag, amylotropic
lateral sclerosis (ALS), cognitive dysfunction, tinnitus,
hypertension, bulimia, anorexia, obesity, cardiac arrythmias,
gastric add hypersecretion, ulcers, pheochromocytoma, progressive
supramuscular palsy, chemical dependencies and addictions (e.g.,
dependencies on, or addictions to nicotine (and/or tobacco
products), alcohol, benzodiazepines, barbituates, opioids or
cocaine), headache, stroke, traumatic brain injury (TBI),
psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia,
dyslexia, multi-infarct dementia, age related cognitive decline,
epilepsy, including petit mal absence epilepsy, senile dementia of
the Alzheimer's type (AD), Parkinson's disease (PD), attention
deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a
mammal, comprising an amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof, that is effective in
treating such disorder or condition and a pharmaceutically
acceptable carrier.
[0090] The present invention also relates to a method of treating a
disorder or condition selected from inflammatory bowel disease
(including but not limited to ulcerative colitis, pyoderma
gangrenosum and Crohn's disease), irritable bowel syndrome, spastic
dystonia, chronic pain, acute pain, celiac sprue, pouchitis,
vasoconstriction, anxiety, panic disorder, depression, bipolar
disorder, autism, sleep disorders, jet lag, amyotropic lateral
sclerosis (ALS), cognitive dysfunction, tinnitus, hypertension,
bulimia, anorexia, obesity, cardiac arrythmias, gastric acid
hypersecretion, ulcers, pheochromocytoma, progressive supramuscular
palsy, chemical dependencies and addictions (e, dependencies on, or
addictions to nicotine (and/or tobacco products), alcohol,
benzodiazepines, barbituates, opioids or cocaine), headache,
stroke, traumatic brain injury (TBI), psychosis, Huntington's
Chorea, tardive dyskinesia, hyperkinesia, dyslexia, multi-infarct
dementia, age related cognitive decline, epilepsy, including petit
mal absence epilepsy, senile dementia of the Alzheimer's type (AD),
Parkinson's disease (PD), attention deficit hyperactivity disorder
(ADHD) and Tourette's Syndrome in a mammal, comprising
administering to a mammal in need of such treatment an amount of a
compound of the formula I, or a pharmaceutically acceptable salt
thereof, that is effective in treating such disorder or
condition.
[0091] The present invention also relates to a pharmaceutical
composition for treating a disorder or condition selected from
inflammatory bowel disease (including but not limited to ulcerative
colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel
syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue,
pouchitis, vasoconstriction, anxiety, panic disorder, depression,
bipolar disorder, autism, sleep disorders, jet lag, amyotropic
lateral sclerosis (ALS), cognitive dysfunction, tinnitus,
hypertension, bulimia, anorexia, obesity, cardiac arrythmias,
gastric acid hypersecretion, ulcers, pheochromocytoma, progressive
supramuscular palsy, chemical dependencies and addictions (e.g.,
dependencies on, or addictions to nicotine (and/or tobacco
products), alcohol, benzodiazepines, barbituates, opioids or
cocaine), headache, stroke, traumatic brain injury (TBI),
psychosis, Huntington's Chorea, tardive dyskinesia, hyperkinesia,
dyslexia, multi-infarct dementia, age related cognitive decline,
epilepsy, including petit mal absence epilepsy, senile dementia of
the Alzheimer's type (AD), Parkinson's disease (PD), attention
deficit hyperactivity disorder (ADHD) and Tourette's Syndrome in a
mammal, comprising an .alpha.7 nicotinic receptor agonizing amount
of a compound of the formula I, or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
[0092] The present invention also relates to a method of treating a
disorder or condition selected from inflammatory bowel disease
(including but not limited to ulcerative colitis, pyoderma
gangrenosum and Crohn's disease), irritable bowel syndrome, spastic
dystonia, chronic pain, acute pain, celiac sprue, pouchitis,
vasoconstriction, anxiety, panic disorder, depression, bipolar
disorder, autism, sleep disorders, jet lag, amyotropic lateral
sclerosis (ALS), cognitive dysfunction, tinnitus, hypertension,
bulimia, anorexia, obesity, cardiac arrythmias, gastric acid
hypersecretion, ulcers, pheochromocytoma, progressive supramuscular
palsy, chemical dependencies and addictions (e.g., dependencies on,
or addictions to nicotine (and/or tobacco products), alcohol,
benzodiazepines, barbituates, opioids or cocaine), headache,
stroke, traumatic brain injury (TBI), psychosis, Huntington's
Chorea, tardive dyskinesia, hyperkinesia, dyslexia, multi-infarct
dementia, age related cognitive decline, epilepsy, including petit
mal absence epilepsy, senile dementia of the Alzheimer's type (AD),
Parkinson's disease (PD), attention deficit hyperactivity disorder
(ADHD) and Tourette's Syndrome in a mammal, comprising
administering to a mammal in need of such treatment an .alpha.7
nicotinic receptor agonizing amount of a compound of the formula I,
or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0093] Compounds of the formula I can be readily prepared according
to the methods described below. In the reaction schemes and
discussion that follow, m, n, o, A, B, Q, D, and E, unless
otherwise indicated, are defined as they are above in the
definition of compounds of the formula I.
[0094] As used herein, the expression "inert reaction solvent"
refers to a solvent system in which the components do not interact
with starting materials, reagents, or intermediates of products in
a manner which adversely affects the yield of the desired
product.
[0095] During any of the following synthetic sequences it may be
necessary and/or desirable to protect sensitive or reactive groups
on any of the molecules concerned. This may be achieved by means of
conventional protecting groups, such as those described in T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1999. 2
[0096] Compounds of the formula I wherein A is an oxygen or sulfur
atom can be prepared as illustrated in Scheme 1. Referring to
Scheme 1, a compound of the formula II is reacted with a compound
of the formula III wherein A is oxygen or sulfur and L is a leaving
group (e.g., choride, bromide, methyl sulfide, alkyl sulfide, aryl
sulfide, alkyl sulfoxide, or aryl sulfoxide) in the presence or
absence of base (e.g., triethylamine, diisopropylamine, pyridine,
2,6-lutidine, sodium or potassium hydroxide, sodium or potassium or
cesium carbonate, sodium or potassium tert-butoxide,
diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-e- ne) in
the presence or absence of an inert reaction solvent such as water,
methanol, ethanol, isopropanol, acetonitrile, methylene chloride,
chloroform, 1,2-dichloroethane, tetrahydrofuran, diethylether,
dioxane, 1,2-dimethoxyethane, benzene, toluene, dimethylformamide,
or dimethylsulfoxide. This reaction is typically carried out at a
temperature from about -10.degree. C. to about 150.degree. C. In
one set of preferred conditions, when A is oxygen, L is
methylsulfide and the reaction is carried out in the absence of
solvent at a temperature from about 70.degree. C. to about
120.degree. C. In a second set of preferred conditions, when A is
oxygen, L is chloride and the reaction is carried out in the
presence of triethylamine, diisopropylethylamine, or sodium
tert-butoxide in a solvent selected from chloroform, methylene
chloride and toluene at a temperature from about 0.degree. C. to
about 50.degree. C. 3
[0097] Compounds of the formula I wherein A is NR.sup.1 can be
prepared as illustrated in Scheme 2. Referring to Scheme 2,
treatment of a compound of the formula II with a compound of the
formula IV wherein X is equal to chlorine, bromine, iodine or
trimethylmethanesulfonate, preferably chlorine or bromine, affords
the desired compound of formula I. This reaction is generally
carried out using a palladium catalyst such as palladium (0)
tetrakis(triphenylphosphine), palladium (II) acetate, allyl
palladium chloride dimer, tris(dibenzylideneacetone)dipalladium
(0), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct,
palladium (II) chloride or
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct, preferably
tris(dibenzylideneacetone)dipalla- dium (0), in the presence or
absence of a phosphine ligand such as
1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine,
tri-o-tolylphosphine, tri-tert-butylphosphine,
1,2-bis(diphenylphosphino)- ethane,
1,3-bis(diphenylphosphino)propane, 2,2'-bis(diphenylphosphino)-1,1-
'-binaphthyl, 2-biphenyl dicyclohexylphosphine,
2-biphenyl-di-tert-butylph- osphine,
2-(N,N-dimethylamino)-2'-di-tert-butylphosphinobiphenyl or
2-(N,N-dimethylamino-2'-dicyclohexylphosphinobiphenyl, preferably
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, in the presence of a
base such as potassium acetate, sodium acetate, cesium acetate,
sodium tert-butoxide, potassium tert-butoxide, sodium carbonate,
lithium carbonate, potassium carbonate, cesium carbonate or cesium
fluoride, preferably sodium tert-butoxide. Suitable reaction inert
solvents for this reaction include, but are not limited to,
1,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran,
ethanol, methanol, 2-propanol and toluene. The preferred solvent is
toluene. Suitable reaction temperatures can range from about
0.degree. C. to about 200.degree. C., and are preferably from about
80.degree. C. to about 120.degree. C.
[0098] Compounds of the formula II can be prepared using methods
analogous to those reported in the literature, see: Rubstov, M. V.;
Mikhlina, E. E.; Vorob'eva, V. Ya.; Yanina, A. Zh. Obshch. Khim.
(1964), V34, 2222-2226. Compounds of formula III and formula IV can
also be prepared by methods analogous to those reported in the
literature, see: Lok, R.; Leone, R. E.; Williams, A. J. J. Org.
Chem. (1996), 61, 3289-3297; Yamato, M.; Takeuchi, Y.; Hashigaki,
K.; Hirota, T. Chem. Pharm. Bull. (1983), 31, 733-736; Chu-Moyer,
M. Y.; Berger, R. J. Org. Chem. (1995), 60, 5721-5725; Sato, Y.;
Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.; Nizato, T.;
Suzuki, K.; Konno, F. J. Med. Chem. (1998), 41, 3015-3021 and Van
Allan, J. A.; Deacon, B. D. Organic Syntheses; Wiley: New York
(1963); Collect. Vol. IV, pp 569-70. 4
[0099] Compounds of the formula I wherein one of the substituents
on B, Q, D or E is equal to NR.sup.6R.sup.7 can be prepared as
illustrated in Scheme 3. Referring to Scheme 3, treatment of a
compound of formula V wherein one of the substituents on B, Q, D or
E is substituted with a nitro group with reducing conditions such
as but not limited to zinc, En or iron and acid, catalytic
hydrogenation, tranfer hydrogenolysis or sodium hydrosulfite in an
inert reaction solvent such as water, methanol, ethanol,
isopropanol, with the preferred conditions being catalytic
hydrogenation using palladium on carbon as a catalyst in ethanol at
ambient temperature and 50 psi of hyrdogen affords a compound of
formula VI wherin the nitro group has been converted to a primary
amine. The compound of formula VI can then be treated with a
compound of formula VII wherein F and G are defined as R.sup.6 and
R.sup.7 above and a reducing agent such as but not limited to
sodium triacetoxyborohydride, sodium borohydride, sodium
cyanoborohydride, lithium aluminum hydride, catalytic hydrogenation
or transfer hydrogenolysis in the presence or absence of an acid
such as but not limited to acetic acid, hydrochloric acid,
trifluoroacetic acid, sulfuric acid, phosphoric acid or nitric acid
in an inert reaction solvent such as chloroform, dichloromethane,
1,2-dichloroethane, acetonitrile, toluene, benzene, ethanol,
methanol or water at 0.degree. C. to 100.degree. C. with the
preferred conditions being sodium triacetoxyborohydride in
1,2-dichloroethane at 25.degree. C. to 90.degree. C. to afford a
compound of formula VIII.
[0100] Also referring to Scheme 3, a compound of formula VI and be
reacted with a compound of formula IX in which R.sup.6 is as
defined above and L is a leaving group (e.g., Cl, Br, I,
OSO.sub.2alkyl, OSO.sub.2aryl) in the presence or absence of base
(e.g., sodium or potassium hydroxide, sodium or potassium or cesium
carbonate, sodium or potassium tert-butoxide, sodium or potassium
hydrogen carbonate, sodium or potassium acetate) in the presence or
absence of an inert reaction solvent such as water, methanol,
ethanol, isopropanol, acetonitrile, methylene chloride, chloroform,
1,2-dichloroethane, tetrahydrofuran, diethylether, dioxane,
1,2-dimethoxyethane, benzene, toluene, dimethylformamide, or
dimethylsulfoxide at a temperature from about -10.degree. C. to
about 150.degree. C. to produce a compound of formula X. The
preferred condition are L=Br, in ethanol at 25.degree. C. to
78.degree. C. 5
[0101] Scheme 4 illustrates an alternative preparation of compounds
of the formula I wherein B, Q, D, or E is Cl, Br, I or wherein B,
Q, D, or E is optionally substituted with a (C.sub.6-C.sub.11)aryl
or 5-12 membered heteroaryl (R.sup.6) group. Referring to Scheme 4,
treatment of a compound of the formula XI with a halogenating
reagent such as but not limited to Cl.sub.2, Br.sub.2, I.sub.2,
N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide in an
inert reaction solvent such as water, acetic acid, methanol,
ethanol, tetrhydrofuran, carbon tetrachloride, chloroform,
acetonitrile or mixtures thereof in the presence or absence of a
base such as potassium acetate, sodium acetate, cesium acetate,
sodium carbonate, lithium carbonate, potassium carbonate, cesium
carbonate, cesium fluoride n-butyllithium, lithium diisopropyl
amide at -78.degree. C. to 100.degree. C.; preferable Br.sub.2 in
water and acetic acid with sodium acetate at 25.degree. C. to
100.degree. C. produces a compound of formula XIII where Z is Br.
Alternatively, a compound of formula XIII where Z=OTf can be
prepared by reaction of a compound of formula XII wherein one of
the substituents on B, Q, D, or E is a hydroxy group with
trifluoroacetic anyhydride, N-phenyltrifluoromethanesulfonimide, or
2-[N,N-bis(trifluoromethylsulfony- l)amino]-5-chloropyridine in the
presence of a base such as but not limited to triethylamine,
diethylisopropylamine, lithium diisopropyl amide, potassium
diisopropyl amide, lithium hexamethyldisilazide, potassium
hexamethyldisilazide, pyridine, lutidine, collidine, sodium or
potassium hydroxide, sodium or potassium or cesium carbonate,
sodium or potassium tert-butoxide, sodium or potassium hydrogen
carbonate, sodium or potassium acetate in an inert reaction solvent
such as ether, tetrahydrofuran, 1,2-dimethoxyethane, dioxanes,
methylene chloride, chloroform, benzene, toluene at -78.degree. C.
to 100.degree. C.; preferable N-phenyltrifluoromethanesulfonimide,
lithium diisopropyl amide in THF at -78.degree. C. to 25.degree.
C.
[0102] Referring to Scheme 4, a compound of the formula I wherein
B, Q, D, or E is optionally substituted with a
(C.sub.6-C.sub.11)aryl or 5-12 membered heteroaryl (R.sup.6) group
can be prepared from a compound of formula XIII wherein Z is
chloro, bromo, iodo or triflate (OTf) by first reacting it with
bis(pinacolato)diboron and a palladium catalyst such as palladium
(0) tetrakis(triphenylphosphine), palladium (II) acetate, allyl
palladium chloride dimer, tris(dibenzylideneacetone)dipalladium
(0), tris(dibenzylidene-acetone)dipalladium (0) chloroform adduct,
palladium (II) chloride or
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct, preferably
dichloro[1,1'-bis(diphenylphosphi- no)ferrocene]palladium (II)
dichloromethane adduct, in the presence or absence of a phosphine
ligand such as 1,1'-bis(diphenylphosphino)ferrocen- e,
triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine,
1,2-bis(diphenylphosphino)ethane,
1,3-bis(diphenylphosphino)propane, BINAP, 2-biphenyl
dicyclohexylphosphine, 2-biphenyl-di-tert-butylphosphin- e,
2-(N,N-dimethylamino)-2'-di-tert-butylphosphino-biphenyl or
2-(N,N-dimethylamino)-2'-dicyclohexylphosphinobiphenyl, preferably
1,1'-bis(diphenylphosphino)ferrocene, and in the presence or
absence of a base such as potassium acetate, sodium acetate, cesium
acetate, sodium carbonate, lithium carbonate, potassium carbonate,
cesium carbonate or cesium fluoride, preferably potassium acetate,
to yield a compound of the formula XIV wherein the Z group has been
replaced with M, wherein M=borane pinacol ester. Generally, this
reaction is carried out in a reaction inert solvent such as
1,4-dioxane, acetonitrile, methyl sulfoxide, tetrahydrofuran,
ethanol, methanol, 2-propanol, toluene, preferably methyl
sulfoxide, at a temperature from about from 0.degree. C. to about
200.degree. C., preferably from about 80.degree. C. to about
120.degree. C.
[0103] Other methods of converting a compound of the formula XIII
with the Z group mentioned above into a compound of the formula XIV
wherein the Z group is replaced with M, wherein M is boronic acid,
boronic acid ester or trialkylstannane, are known in the art. For
instance, treatment of a compound of the formula XIII, wherein Z is
Br or I, with an alkyl lithium reagent such as, but not limited to
n-butyl lithium, sec butyl lithium or tert-butyl lithium, in a
solvent such as diethyl ether, tetrahydrofuran,
1,2-dimethoxyethane, hexane, toluene, dioxane or a similar reaction
inert solvent, at a temperature from about -100.degree. C. to about
25.degree. C. affords the corresponding compound of the formula XIV
wherein Z is Li. Treatment of a solution of this material with a
suitable boronic ester such as trimethoxyborane, triethoxyborane or
triisopropylborane, followed by a standard aqueous work-up with
acid will afford the corresponding compound of the formula XIV
wherein M is boronic acid.
[0104] Alternatively, treating a mixture of a compound of the
formula XIII wherein Z is Br or I and a boronic ester with an alkyl
lithium reagent, as described above, followed by a standard aqueous
work-up with acid will afford the corresponding compound of formula
XIV wherein M is boronic acid. Alternatively, treating a compound
of the formula XIII wherein Z is Br or I with an alkyl lithium
reagent such as, but not limited to n-butyl lithium, sec butyl
lithium or tert-butyl lithium, in a solvent such as diethyl ether,
tetrahydrofuran, dimethoxyethane, hexane, toluene, dioxane or a
similar reaction inert solvent, at a temperature from about
-100.degree. C. to about 25.degree. C. will afford the
corresponding compound of the formula XIV wherein M is Li.
Treatment of a solution of this material with a suitable
trialkylstannyl halide such as, but not limited to trimethylstannyl
chloride or bromide or tributylstannyl chloride or bromide,
followed by a standard aqueous work-up will afford the
corresponding compound of the formula XIV wherein M is trimethyl or
tributylstannane.
[0105] Referring to Scheme 4, treatment of a compound of the
formula XIV wherein M is a boronic acid, boronic ester, or
trialkylstannane group, with an aryl or heteroaryl chloride, aryl
or heteroaryl bromide, aryl or heteroaryl iodide, or aryl or
heteroaryl triflate of the formula XIV, preferably an aryl or
heteroaryl bromide, with a palladium catalyst such as palladium (0)
tetrakis(triphenylphosphine), palladium (II) acetate, allyl
palladium chloride dimer, tris(dibenzylideneacetone)dipalladium
(0), tris(dibenzylideneacetone)dipalladium (0) chloroform adduct,
palladium (II) chloride or
dichloro[1,1'-bis(diphenylphosphino)ferrocene]- palladium (II)
dichloromethane adduct, preferably dichloro[1,1'-bis(diphen-
ylphosphino)ferrocene]palladium (II) dichloromethane adduct, in the
presence or absence of a phosphine ligand such as
1,1'-bis(diphenylphosph- ino)ferrocene, triphenylphosphine,
tri-o-tolylphosphine, tri-tert-butylphosphine,
1,2-bis(diphenylphosphino)ethane,
1,3-bis(diphenylphosphino)-propane, BINAP, 2-biphenyl
dicyclohexylphosphine, 2-biphenyl-di-tert-butylphosphine,
2-(N,N-dimethylamino)-2'-di-tert-butylphosphino-biphenyl or
2-(N,N-dimethylamino)-2'-dicyclohexylphosphinobiphenyl, preferably
1,1'-bis(diphenylphosphino)ferrocene, and in the presence or
absence of a base such as potassium phosphate, potassium acetate,
sodium acetate, cesium acetate, sodium carbonate, lithium
carbonate, potassium carbonate, cesium fluoride or cesium
carbonate, preferably potassium phosphate, affords a compound of
formula XVII. This reaction is typically carried out in a reaction
inert solvent such as 1,4-dioxane, acetonitrile, methyl sulfoxide,
tetrahydrofuran, ethanol, methanol, 2-propanol, or toluene,
preferably 1,4-dioxane, in the presence or absence of from about
1%-about 10% water, preferably about 5% water, at a temperature
from about 0.degree. C. to about 200.degree. C., preferably from
about 60.degree. C. to about 100.degree. C.
[0106] Referring to Scheme 4, altematively, a compound of the
formula XIII can be reacted with a compound of the formula XVI,
wherein M is a boronic acid, boronic acid ester, borane pinacol
ester or trialkylstannane group, in the presence of a palladium
catalyst such as palladium (0) tetrakis(triphenylphosphine),
palladium (II) acetate, allyl palladium chloride dimer,
tris(dibenzylideneacetone)dipalladium (0),
tris(dibenzylideneacetone)dipalladium (0) chloroform adduct,
palladium (II) chloride or
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane adduct, preferably palladium (II) acetate, in the
presence or absence of a phosphine ligand such as
1,1'-bis(diphenylphosph- ino)ferrocene, triphenylphosphine,
triotolylphosphine, tri-tert-butylphosphine,
1,2-bis(diphenylphosphino)ethane,
1,3-bis(diphenylphosphino)propane, BINAP, 2-biphenyl
dicyclohexylphosphine, 2-biphenyl-di-tert-butylphosphine,
2-(N,N-dimethylamino)-2'-di-tert-butylphosphino-biphenyl or
2-(N,N-dimethylamino)-2'-dicyclohexylphosphinobiphenyl, preferably
2-(N,N-dimethylamino)-2'-dicyclohexylphosphinobiphenyl, and in the
presence or absence of a base such as potassium phosphate,
potassium acetate, sodium acetate, cesium acetate, sodium
carbonate, lithium carbonate, potassium carbonate, cesium fluoride
or cesium carbonate, preferably cesium fluoride, affords a compound
of formula XVII. This reaction is typically carried out in a
reaction inert solvent such as 1,4-dioxane, 1,2-dimethoxyethane,
acetonitrile, methyl sulfoxide, tetrahydrofuran, ethanol, methanol,
2-propanol, or toluene, preferably 1,2-dimethoxyethane, in the
presence or absence of from about 1% to about 10% triethylamine,
preferably about 1% triethylamine, at a temperature from about
0.degree. C. to about 200.degree. C., preferably from about
60.degree. C. to about 100.degree. C.
[0107] Isolation and purification of the products can be
accomplished by standard procedures that are known to a chemist of
ordinary skill.
[0108] In each of the reactions discussed above, or illustrated in
Schemes 1-4, above, pressure is not critical unless otherwise
indicated. Pressures from about 0.5 atmospheres to about 5
atmospheres are generally acceptable, with ambient pressure, i.e.,
about 1 atmosphere, being preferred as a matter of convenience.
[0109] The compounds of the formula I and their pharmaceutically
acceptable salts (hereafter "the active compounds") can be
administered via either the oral, transdermal (e.g., through the
use of a patch), intranasal, sublingual, rectal, parenteral or
topical routes. Transdermal and oral administration are preferred.
These compounds are, most desirably, administered in dosages
ranging from about 0.25 mg up to about 1500 mg per day, preferably
from about 0.25 to about 300 mg per day in single or divided doses,
although variations will necessarily occur depending upon the
weight and condition of the subject being treated and the
particular route of administration chosen. However, a dosage level
that is in the range of about 0.01 mg to about 10 mg per kg of body
weight per day is most desirably employed. Variations may
nevertheless occur depending upon the weight and condition of the
persons being treated and their individual responses to said
medicament, as well as on the type of pharmaceutical formulation
chosen and the time period and interval during which such
administration is carried out In some instances, dosage levels
below the lower limit of the aforesaid range may be more than
adequate, while in other cases still larger doses may be employed
without causing any harmful side effects, provided that such larger
doses are first divided into several small doses for administration
throughout the day.
[0110] The active compounds can be administered alone or in
combination with pharmaceutically acceptable carriers or diluents
by any of the several routes previously indicated. More
particularly, the active compounds can be administered in a wide
variety of different dosage forms, e.g., they may be combined with
various pharmaceutically acceptable inert carriers in the form of
tablets, capsules, transdermal patches, lozenges, troches, hard
candies, powders, sprays, creams, salves, suppositories, jellies,
gels, pastes, lotions, ointments, aqueous suspensions, injectable
solutions, elixirs, syrups, and the like. Such carriers include
solid diluents or fillers, sterile aqueous media and various
non-toxic organic solvents. In addition, oral pharmaceutical
compositions can be suitably sweetened and/or flavored. In general,
the active compounds are present in such dosage forms at
concentration levels ranging from about 5.0% to about 70% by
weight.
[0111] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate and glycine may be employed
along with various disintegrants such as starch (preferably corn,
potato or tapioca starch), alginic acid and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc can be used for tabletting purposes. Solid
compositions of a similar type may also be employed as fillers in
gelatin capsules; preferred materials in this connection also
include lactose or milk sugar, as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration the active ingredient may be
combined with various sweetening or flavoring agents, coloring
matter and, if so desired, emulsifying and/or suspending agents,
together with such diluents as water, ethanol, propylene glycol,
glycerin and various combinations thereof.
[0112] For parenteral administration, a solution of an active
compound in either sesame or peanut oil or in aqueous propylene
glycol can be employed. The aqueous solutions should be suitably
buffered (preferably pH greater than 8), if necessary, and the
liquid diluent first rendered isotonic. These aqueous solutions are
suitable for intravenous injection purposes. The oily solutions are
suitable for intraarticular, intramuscular and subcutaneous
injection purposes. The preparation of all these solutions under
sterile conditions is readily accomplished by standard
pharmaceutical techniques well known to those skilled in the
art.
[0113] It is also possible to administer the active compounds
topically and this can be done by way of creams, a patch, jellies,
gels, pastes, ointments and the like, in accordance with standard
pharmaceutical practice.
[0114] The effectiveness of the active compounds in suppressing
nicotine binding to specific receptor sites can be determined by
the following procedure, which is a modification of the methods of
Lippiello, P. M. and Fernandes, K. G. (in "The Binding of
L-[.sup.3H]Nicotine To A Single Class of High-Affinity Sites in Rat
Brain Membranes", Molecular Pharm., 29, 448-54, (1986)) and
Anderson, D. J. and Americ, S. P. (in "Nicotinic Receptor Binding
of .sup.3H-Cystsine, .sup.3H-Nicotine and
.sup.3H-Methylcarmbamylcholine In Rat Brain", European J. Pharm.,
253, 261-67 (1994)). Male Sprague-Dawley rats (200-300 g) from
Charles River were housed in groups in hanging stainless steel wire
cages and were maintained on-a 12 hour light/dark cycle (7 a.m.-7
p.m. light period). They received standard Purina Rat Chow and
water ad libitum. The rats were killed by decapitation. Brains were
removed immediately following decapitation. Membranes were prepared
from brain tissue according to the methods of Lippiello and
Fernandez (Molec. Pharmacol., 29, 448-454, (1986)) with some
modifications. Whole brains were removed, rinsed with ice-cold
buffer, and homogenized at 0.degree. in 10 volumes of buffer (w/v)
using a Brinkmann Polytron.TM. (Brinkmann Instruments Inc.,
Westbury, N.Y.), setting 6, for 30 seconds. The buffer consisted of
50 mM Tris HCl at a pH of 7.5 at room temperature. The homogenate
was sedimented by centrifugation (10 minutes; 50,000.times.g;
0.degree. to 4.degree. C.). The supernatant was poured off and the
membranes were gently resuspended with the Polytron and centrifuged
again (10 minutes; 50,000.times.g; 0.degree. C. to 4.degree. C.).
After the second centrifugation, the membranes were resuspended in
assay buffer at a concentration of 1.0 g/100 mL. The composition of
the standard assay buffer was 50 mM Tris HCl, 120 mM NaCl, 5 mM
KCl, 2 mM MgCl.sub.2, 2 mM CaCl.sub.2 and had a pH of 7.4 at room
temperature.
[0115] Routine assays were performed in borosilicate glass test
tubes. The assay mixture typically consisted of 0.9 mg of membrane
protein in a final incubation volume of 1.0 mL. Three sets of tubes
were prepared wherein the tubes in each set contained 50 .mu.L of
vehicle, blank, or test compound solution, respectively. To each
tube was added 200 .mu.L of [.sup.3H]-nicotine in assay buffer
followed by 750 .mu.L of the membrane suspension. The final
concentration of nicotine in each tube was 0.9 nM. The final
concentration of cytisine in the blank was 1 .mu.M. The vehicle
consisted of deionized water containing 30 .mu.L of 1 N acetic acid
per 50 mL of water. The test compounds and cytisine were dissolved
in vehicle. Assays were initiated by vortexing after addition of
the membrane suspension to the tube. The samples were incubated at
0.degree. to 4.degree. C. in an iced shaking water bath.
Incubations were terminated by rapid filtration under vacuum
through Whatman GF/B.TM. glass fiber filters (Brandel Biomedical
Research & Development Laboratories, Inc., Gaithersburg, Md.)
using a Brandel.TM. multi-manifold tissue harvester (Brandel
Biomedical Research & Development Laboratories, Inc.,
Gaithersburg, Md.). Following the initial filtration of the assay
mixture, filters were washed two times with ice-cold assay buffer
(5 ml each). The filters were then placed in counting vials and
mixed vigorously with 20 ml of Ready Safe.TM. (Beckman, Fullerton,
Calif.) before quantification of radioactivity. Samples were
counted in a LKB Wallac Rackbeta.TM. liquid scintillation counter
(Wallac Inc., Gaithersburg, Md.) at 40-50% efficiency. All
determinations were in triplicate.
[0116] Calculations: Specific binding (C) to the membrane is the
difference between total binding in the samples containing vehicle
only and membrane (A) and non-specific binding in the samples
containing the membrane and cytisine (B), i.e.,
[0117] Specific binding=(C)=(A)-(B).
[0118] Specific binding in the presence of the test compound (E) is
the difference between the total binding in the presence of the
test compound (D) and non-specific binding (B), i.e.,
(E)=(D)-(B).
% Inhibition=(1-((E)/(C)) times 100.
[0119] The compounds of the invention that were tested in the above
assay exhibited IC.sub.50 values of less than 100 .mu.M.
[0120] [.sup.125I]-Bungarotoxin binding to nicotinic receptors in
GH.sub.4Cl cells: Membrane preparations were made for nicotinic
receptors expressed in GH.sub.4Cl cell line. Briefly, one gram of
cells by wet weight were homogenized with a polytron in 25 mls of
buffer containing 20 mM Hepes, 118 mM NaCl, 4.5 mM KCl, 2.5 mM
CaCl.sub.2, 1.2 mM MgSO.sub.4, pH 7.5. The homogenate was
centrifuged at 40,000.times.g for 10 min at 4.degree. C., the
resulting pellet was homogenized and centrifuged again as described
above. The final pellet was resuspended in 20 mls of the same
buffer. Radioligand binding was carried out with [.sup.125I]
alpha-bungarotoxin from New England Nuclear, specific activity
about 16 uCi/ug, used at 0.4 nM final concentration in a 96 well
microtiter plate. The plates were incubated at 37.degree. C. for 2
hours with 25 .mu.l drugs or vehicle for total binding, 100 .mu.l
[.sup.125I] Bungarotoxin and 125 .mu.l tissue preparation.
Nonspecific binding was determined in the presence of
methyllycaconitine at 1 .mu.M final concentration. The reaction was
terminated by filtration using 0.5% Polyethylene imine treated
Whatman GF/B.TM. glass fiberfilters (Brandel Biomedical Research
& Development Laboratories, Inc., Gaithersburg, Md.) on a
Skatron cell harvester (Molecular Devices Corporation, Sunnyvale,
Calif.) with ice-cold buffer, filters were dried overnight, and
counted on a Beta plate counter using Betaplate Scint. (Wallac
Inc., Gaithersburg, Md.). Data are expressed as IC50's
(concentration that inhibits 50% of the specific binding) or as an
apparent Ki, IC50/1+[L]/KD. [L]=ligand concentration, KD=affinity
constant for [.sup.125I] ligand determined in separate
experiment.
[0121] The compounds of the invention that were tested in the above
assay exhibited IC.sub.50 values of less than 10 .mu.M.
[0122] [.sup.125I]-Bungarotoxin binding to alpha1 nicotinic
receptors in Torpedo electroplax membranes: Frozen Torpedo
electroplax membranes (100 .mu.l) were resuspended in 213 mls of
buffer containing 20 mM Hepes, 118 mM NaCl, 4.5 mM KCl, 2.5 mM
CaCl.sub.2, 1.2 mM MgSO.sub.4, pH 7.5 with 2 mg/ml BSA. Radioligand
binding was carried out with [.sup.125I] alpha-bungarotoxin from
New England Nuclear, specific activity about 16 uCi/ug, used at 0.4
nM final concentration in a 96 well microtiter plate. The plates
were incubated at 37.degree. C. for 3 hours with 25 .mu.l drugs or
vehicle for total binding, 100 .mu.l [.sup.125I] Bungarotoxin and
125 .mu.l tissue preparation. Nonspecific binding was determined in
the presence of alpha-bungarotoxin at 1 .mu.M final concentration.
The reaction was terminated by filtration using 0.5% Polyethylene
imine treated GF/B filters on a Brandel cell harvester with
ice-cold buffer, filters were dried overnight, and counted on a
Beta plate counter using Betaplate Scint. Data are expressed as
IC50's (concentration that inhibits 50% of the specific binding) or
as an apparent Ki, IC50/1+[L]/KD. [L]=ligand concentration,
KD=affinity constant for [.sup.125I] ligand determined in separate
experiment.
[0123] The compounds of the invention that were tested in the above
assay exhibited IC.sub.50 values of less than 100 .mu.M.
[0124] 5-HT.sub.3 Receptor Binding in NG-108 Cells Using
3H-LY278584: NG-108 cells endogenously express 5-HT.sub.3
receptors. Cells are grown in DMEM containing 10% fetal bovine
serum supplemented with L-glutamine (1:100). Cells are grown to
confluence and harvested by removing the media, rinsing the flasks
with phosphate buffered saline (PBS) and then allowed to sit for a
2-3 minutes with PBS containing 5 mM EDTA. Cells are dislodged and
poured into a centrifuge tube. Flasks are rinsed with PBS and added
to centrifuge tube. The cells are centrifuged for ten minutes at
40,000.times.g (20,000 rpm in Sorvall SS34 rotor(Kendro Laboratory
Products, Newtown, Conn.)). The supernatant is discarded (into
chlorox) and at this point the remaining pellet is weighed and can
be stored frozen (-80 degrees C.) until used in the binding assay.
Pellets (fresh or frozen -250 mgs per 96 well plate) are
homogenized in 50 mM Tris HCl buffer containing 2 mM MgCl.sub.2 (pH
7.4) using a Polytron homogenizer (setting 15,000 rpm) for ten
seconds. The homogenate is centrifuged for ten minutes at
40,000.times.g. The supernatant is discarded and the pellet
resuspended with the Polytron in fresh ice-cold 50 mM Tris HCl
containing 2 mM MgCl.sub.2 (pH 7.4) buffer and centrifuged again.
The final pellet is resuspended in assay buffer (50 mM Tris HCl
buffer (pH 7.4 at 37.degree. C. degrees) containing 154 mM NaCl,)
for a final tissue concentration of 12.5 mg per mL buffer
(1.25.times. final concentration). Incubations were initiated by
the addition of tissue homogenate to 96 well polypropylene plates
containing test compounds that have been diluted in 10% DMSO/50 mM
Tris buffer and radioligand (1 nM final concentration of
3H-LY278584). Nonspecific binding was determined using a saturating
concentration of a known potent 5-HT.sub.3 antagonist (10 .mu.M
ICS-205930). After an hour incubation at 37.degree. C. in a water
bath, the incubation is ended by rapid filtration under vacuum
through a fire-treated Whatman GF/B glass fiber filter (presoaked
in 0.5% Polyethylene imine for two hours and dried) using a 96 well
Skatron Harvester (3 sec pre-wet; 20 seconds wash; 15 seconds dry).
Filters are dried overnight and then placed into Wallac sample bags
with 10 mLs BetaScint. Radioactivity is quantified by liquid
scintillation counting using a BetaPlate counter (Wallac,
Gaithersburg, Md.). The percent inhibition of specific binding is
calculated for each concentration of test compound. An IC50 value
(the concentration which inhibits 50% of the specific binding) is
determined by linear regression of the concentration response data
(log concentration vs. logit percent values). Ki values are
calculated according to Cheng & Prusoff-Ki=IC50/(1+(L/Kd)),
where L is the concentration of the radioligand used in the
experiment and the Kd value is the dissociation constant for the
radioligand determined in separate saturation experiments.
[0125] The compounds of the invention that were tested in the above
assay exhibited IC.sub.50 values of less than 100 .mu.M.
[0126] The following experimental examples illustrate but do not
limit the present invention. In the examples, commercial reagents
were used without further purification. Purification by
chromatography was done on prepacked silica columns from Biotage
(Dyax Corp, Biotage Division, Charlottesville, Va.). Melting points
(mp) were obtained using a Mettler Toledo FP62 melting point
apparatus (Mettler-Toledo, Inc., Worthington, Ohio) with a
temperature ramp rate of 10.degree. C./min and are uncorrected.
Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
recorded in deuterated solvents on a Varian INOVA400 (400 MHz)
spectrometer (Varian NMR Systems, Palo Alto, Calif.). Chemical
shifts are reported in parts per million (ppm, .delta.) relative to
Me.sub.4Si (.delta. 0.00). Proton NMR splitting patterns are
designated as singlet (s), doublet (d), triplet (t), quartet (q),
quintet (quin), sextet (sex), septet (sep), multiplet (m) apparent
(ap) and broad (br). Coupling constants are reported in hertz (Hz).
Carbon-13 nuclear magnetic resonance (.sup.13C NMR) spectra were
recorded on a Varian INOVA400 (100 MHz). Chemical shifts are
reported in ppm (.delta.) relative to the central line of the 1:1:1
triplet of deuterochloroform (.delta. 77.00), the center line of
deuteromethanol (.delta. 49.0) or deuterodimethylsulfoxide (.delta.
39.7). The number of carbon resonance's reported may not match the
actual number of carbons in some molecules due to magnetically and
chemically equivalent carbons and may exceed the number of actual
carbons due to conformational isomers. Mass spectra (MS) were
obtained using a Waters ZMD mass spectrometer using flow injection
atmospheric pressure chemical ionization (APCl) (Waters
Corporation, Milford, Mass). Gas chromatography with mass detection
(GCMS) were obtained using a Hewlett Packard HP 6890 series GC
system with a HP 5973 mass selective detector and a HP-1
(crosslinked methyl siloxane) column (Agilent Technologies,
Wilmington, Del.). HPLC spectra were recorded on a Hewlett Packard
1100 series HPLC system with a Zorbax SB-G8, 5 .mu.m, 4.6.times.150
mm column (Agilent Technologies, Wilmington, Del.) at 25.degree. C.
using gradient elution. Solvent A is water, Solvent B is
acetonitrile, Solvent C is 1% trifluoroacetic acid in water. A
linear gradient over four minutes was used starting at 80% A, 10%
B, 10% C and ending at 0% A, 90% B, 10% C. The eluent remained at
0% A, 90% B, 10% C for three minutes. A linear gradient over one
minute was used to return the eluent to 80% A, 10% B, 10% C and it
was held at this until the run time equaled ten minutes. Room
temperature (RT) refers to 20-25.degree. C. The abbreviations "h"
and "hrs" refer to "hours". 1,4-Diaza-bicyclo[3.2.2]nonane was
prepared via slight modifications of the published procedure: see,
Rubstov, M. V.; Mikhlina, E. E; Vorob'eva, V. Ya.; Yanina, A. Zh.
Obshch. Khim. 1964, V34, 2222-2226.
EXAMPLE 1
4-BENZOOXAZOL-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0127] 2-Chlorobenzoxazole (Aldrich, 99 .mu.L, 0.87 mmol) was added
to a solution of 1,4-diazabicyclo[3.2.2]nonane (100 mg, 0.79 mmol)
in methanol (2.65 mL) at 0.degree. C. The reaction mixture was
allowed to slowly warm to RT. After a period of 16 h iPr.sub.2NEt
(138 .mu.L, 0.79 mmol) was added and the mixture was stirred at RT
for 4.5 h at which time it was diluted with CHCl.sub.3 and
NaHCO.sub.3. The layers were partitioned and the aqueous layer was
extracted with CHCl.sub.3 (.times.3). The combined organic layers
were washed with H.sub.2O and brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated. The crude residue was purified by
chromatography (Biotage, 12L) eluting with 4% MeOH in CHCl.sub.3
containing 20 drops of NH.sub.4OH per liter of eluent to afford 67
mg (35%) of the title compound as a yellow oil: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.30 (d, 1H, J=7.5 Hz), 7.19 (d, 1H,
J=7.9 Hz), 7.10 (t, 1H, J=7.5 Hz), 6.94 (t, 1H, J=7.9 Hz), 4.46,
(s, 1H), 3.87, (t, 2H, J=5.8 Hz), 3.12-2.92 (m, 6H), 2.15-2.05 (m,
2H), 1.79-1.70 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
161.8, 148.9, 143.7, 124.1, 120.3, 116.1, 108.7, 57.3, 50.3, 46.5,
44.4, 27.1; MS (Cl) m/z 244.3 (M+1). The hydrochloride salt was
prepared by dissolving the title compound in iPrOH and adding 0.1
mL of 6 M hydrochloric acid.
EXAMPLE 2
4-BENZOTHIAZOL-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0128] 2-Chlorobenzothiazole (Aldrich, 109 .mu.L, 0.841 mmol) was
added to a solution of 1,4-diazabicyclo[3.2.2]nonane (57%, 169 mg,
0.765 mmol), Et.sub.3N (213 .mu.L, 1.53 mmol) in DMF (2.5 mL). The
reaction mixture was heated at 100.degree. C. for 2 h. The mixture
was allowed to cool to RT, diluted with EtOAc and H.sub.2O and the
layers were partitioned. The aqueous layer was extracted with EtOAc
(3.times.) and the combined organic extracts were washed
successively with H.sub.2O and brine and then dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude residue
was purified by chromatography (Biotage, 12L) eluting with 5% MeOH
in CHCl.sub.3 to afford 68 mg (34%) of the title compound as a
yellow oil: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.58 (d, 1H,
J=7.9 Hz), 7.57 (d, 1H, J=7.9 Hz), 7.27 (t, 1H, J=8.3 Hz), 7.04
(td, 1H, J=7.9, 1.2 Hz), 4.31 (s, 1H), 3.92 (t, 2H, J=5.8 Hz),
3.19-2.98 (m, 6H), 2.25-2.16 (m, 2H), 1.84-1.77 (m, 2H); MS (Cl)
m/z 260.2 (M+1). The hydrochloride salt was prepared by dissolving
the title compound in iPrOH and adding 0.1 mL of 6 M hydrochloric
acid.
[0129] The 2-mercaptobenzoxazoles were prepared by two different
methods and the general procedures are described in the literature,
see: Sato, Y.; Yamada, M.; Yoshida, S.; Soneda, T.; Ishikawa, M.;
Nizato, T.; Suzuki, K.; Konno, F. J. Med. Chem. 1998, 41, 3015-3021
and Van Allan, J. A.; Deacon, B. D. Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, pp 569-70.
EXAMPLE 3
5-PHENYL-3H-BENZOOXAZOLE-2-THIONE
[0130] Carbon disulfide (7.7 mL) was added to a mixture of
2-amino-4-phenylphenol (1.0 g, 5.4 mmol), potassium hydroxide.
(0.36 g, 6.5 mmol) and ethanol (11.7 mL). The flask was fitted with
a reflux condenser and the resulting mixture was placed in an oil
bath at 60.degree. C. for 16 h. After cooling to RT, the mixture
was concentrated and ethyl acetate (20 mL) and 1 M hydrochloric
acid (10 mL) were added to the residue. The layers were partitioned
and the organic layer was washed successively with 1 M HCl, water
and brine. The organic layer was dried (Na.sub.2SO.sub.4), filtered
and concentrated to afford 1.20 g (98%) which was used without
further purification: .sup.1H NMR (d6-DMSO, 400 MHz) .delta. 13.98
(s, 1H), 7.64-7.62 (m, 2H), 7.58-7.49 (m, 2H), 7.46-7.42 (m, 2H),
7.39-7.33 (m, 2H); .sup.13C (d6-DMSO, 400 MHz) .delta. 181.2,
148.4, 140.1, 138.5, 132.7, 129.7, 128.3, 127.7, 123.4, 111.0,
109.1; MS (Cl) m/z 228.1 (M+1); HPLC retention time=3.09 min.
EXAMPLE 4
2-AMINO-4-BROMOPHENOL
[0131] A solution of KOH (5.14 g, 91.7 mmol) in water (33 mL) was
added to 4-bromo-2-nitrophenol (Aldrich, 1.00 g, 4.59 mmol). Sodium
hydrosulfite (7.98 g, 45.9 mmol) was added in one portion. The
mixture was stirred at RT for 30 min. and poured into ethyl acetate
(25 mL). The layers were partitioned and the aqueous layer was
extracted with ethyl acetate (4.times.25 mL). The combined organic
layers were dried (Na.sub.2SO.sub.4), filtered and concentrated to
give 488 mg (56%) of the title compound which was used without
further purification: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
6.77 (d, 1H, J=2.1 Hz), 6.65 (dd, 1H, J=8.3, 2.5 Hz), 6.52 (d, 1H,
J=8.3 Hz); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 144.0, 136.6,
121.7, 118.7, 116.2, 112.1; MS (Cl) m/z 188.0 (M+1); HPLC retention
time=1.10 min.
EXAMPLE 5
5-BROMO-3H-BENZOOXAZOLE-2-THIONE
[0132] Potassium ethyl xanthate (416 mg, 2.60 mmol) was added to a
solution of 2-amino-4-bromophenol (244 mg, 1.30 mmol) in EtOH (3.24
mL). The reaction mixture was heated at reflux for 4 h. Upon
cooling to RT the mixture was concentrated and the resulting
residue was dissolved in water. Acetic acid was added until pH=5
and a white solid precipitated from the solution. The solid was
filtered, washed with water and dried to afford 270 mg (90%) of a
tan powder which was used without further purification: .sup.1H NMR
(d6-DMSO, 400 MHz) .delta. 14.02 (s, 1H), 7.47-7.38 (m, 3H);
.sup.13C (d6-DMSO, 400 MHz) .delta. 181.4, 148.1, 133.7, 127.1,
117.8, 118.8, 112.2; MS (Cl) m/z 229.8 (M-1); HPLC retention
time=4.34 min.
[0133] The 2-chlorobenzoxazole compounds were prepared by the
general procedures described in the literature, see: Lok, R.;
Leone, R. E.; Williams, A. J. J. Org. Chem. 1996, 61,
3289-3297.
EXAMPLE 6
2-CHLORO-5-PHENYLBENZOXAZOLE
[0134] 5-Phenyl-3H-benzooxazole-2-thione (227 mg, 1.0 mmol) was
dissolved in phosphorus oxychloride (1.6 mL). Phosphorus
pentachloride (208 mg, 1.0 mmol) was added and the mixture was
placed in an oil bath at 100.degree. C. for 3 h. The mixture was
allowed to cool to RT and concentrated. The crude residue was
concentrated from CH.sub.2Cl.sub.2 (3.times.). The crude reaction
product was triturated with hexanes (40 mL), and the resulting
solids were collected by filtration. The solids were washed with
hexanes (20 mL.times.3) and dried to afford 1.47 g (73%) of the
title compound: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d,
1H, J=1.3 Hz), 7.60-7.56 (m, 3H), 7.55-7.52 (m, 1H), 7.49-7.44 (m,
2H), 7.40-7.36 (m, 1H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
151.6, 151.4, 141.9, 140.7, 139.3, 129.2, 127.8, 127.7, 125.2,
118.4, 110.7; MS (Cl) m/z 230.1 (M+1); HPLC retention time=5.41
min.
[0135] The 2-methylthiobenzoxazole compounds were prepared by the
general procedures described in the literature, see: Yamato, M.;
Takeuchi, Y.; Hashigaki, K.; Hirota, T. Chem. Pharm. Bull. 1983,
31, 733-736.
EXAMPLE 7
5-BROMO-2-METHYLSULFANYL-BENZOOXAZOLE
[0136] 5-Bromo-3H-benzooxazole-2-thione (530 mg, 2.30 mmol) was
dissolved in DMF (5.75 mL). Potassium carbonate (318 mg, 2.30 mmol)
and iodomethane (172 .mu.L, 2.76 mmol) were added and the reaction
mixture was allowed to stir at RT for 3.5 h. The mixture was
diluted with water (10 mL) and extracted with ethyl acetate
(4.times.10 mL). The combined organic extracts were washed with
water (3.times.10 mL), brine (10 mL) and dried (Na.sub.2SO.sub.4),
filtered and concentrated to afford 538 mg (96%) of the title
compound as a dark brown solid:
[0137] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.72 (d, 1H, J=2.1
Hz), 7.36-7.26 (m, 2H), 2.75 (s, 3H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 167.6, 151.2, 143.8, 126.9, 121.6, 117.3, 111.2, 14.8;
MS (Cl) m/z 244.0 (M+1); HPLC retention time=5.10 min.
EXAMPLE 8
4-(5-PHENYL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0138] 1,4-Diazabicyclo[3.2.2]nonane (504 mg, 4.0 mmol) was added
to a mixture of 2-chloro-5-phenylbenzoxazole (919 mg, 4.0 mmol),
sodium tert-butoxide (423 mg, 4.4 mmol) and toluene (4 mL) at RT.
The mixture was stirred at RT for 16 h and water (10 mL) and ethyl
acetate (10 mL) were added. The layers were partitioned and the
aqueous layer was extracted with ethyl acetate (3.times.10 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated and the residue was purified by chromatography
(Biotage, 40S) eluting with 4% MeOH in CHCl.sub.3 with 20 drops of
NH.sub.4OH per liter of eluent to afford 540 mg (42%) of the title
compound as an oil: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
7.60-7.56 (m, 3H), 7.42 (t, 2H, J=7.7 Hz), 7.33-7.20 (m, 3H), 4.51
(s, 1H), 3.92 (t, 2H, J=5.8 Hz), 3.17-2.97 (m, 6H), 2.20-2.07 (m,
2H), 1.84-1.75 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
162.2, 148.6, 144.3 141.9, 137.9, 129.0, 127.5, 127.1, 119.8,
114.8, 108.8, 57.3, 50.4, 46.5, 44.4, 27.0; MS (Cl) m/z 320.1
(M+1). The hydrochloride salt was prepared by diluting the title
compound in ethyl acetate and adding a 2.5 N HCl in ethyl acetate
solution: mp>300.degree. C.
EXAMPLE 9
4-(5-BROMO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0139] 1,4-Diazabicyclo[3.2.2]nonane (57%, 731 mg, 3.31 mmol) was
added to a solution of 5-bromo-2-methylsulfanyl-benzooxazole (538
mg, 2.20 mmol) in iPrOH (4.4 mL). The mixture was placed in an oil
bath at 90.degree. C. and the solvent was evaporated. The mixture
was allowed to stir neat at 90.degree. C. for 18 h. Upon cooling to
RT the mixture was purified by chromatography (Biotage, 25M)
eluting with 4% MeOH in CHCl.sub.3 with 20 drops of NH.sub.4OH per
liter of eluent to afford 392 mg (55%) of the title compound as an
oil: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.40 (t, 1H, J=1.2
Hz), 7.05 (d, 2H, J=1.2 Hz), 4.46-4.43 (m, 1H), 3.87 (t, 2H, J=5.8
Hz), 3.14-2.93 (m, 6H), 2.13-2.06 (m, 2H), 1.81-1.73 (m, 2H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 162.3, 148.0, 145.6,
122.9, 119.0, 116.8, 109.8, 57.2, 50.5, 46.5, 44.4, 27.0; MS (Cl)
m/z 322.0 (M+1); HPLC retention time=3.36 min. The hydrochloride
salt was prepared by diluting in ethyl acetate and adding a
solution of 2.5 N HCl in ethyl acetate: mp>300.degree. C.
EXAMPLE 10
3H-1-OXA-3-AZA-CYCLOPENTA[B]NAPHTHALENE-2-THIONE
[0140] The title compound was prepared from 3-amino-2-napthol
(Aldrich) by the procedure described in Example 3 in 93% yield:
.sup.1H NMR (d6-DMSO, 400 MHz) .delta. 7.99-7.92 (m, 3H), 7.64 (s,
1H), 7.48-7.42 (m, 2H); .sup.13C (d6-DMSO, 100 MHz) .delta. 182.3,
148.1, 131.7, 131.6, 130.6, 128.7, 128.4, 126.2, 125.9, 106.9,
106.4; MS (Cl) m/z 202.1 (M+1); HPLC retention time=4.46 min.
EXAMPLE 11
2-CHLORO-1-OXA-3-AZA-CYCLOPENTA[B]NAPHTHALENE
[0141] The title compound was prepared from
3H-1-oxa-3-aza-cyclopenta[b]na- phthalene-2-thione by the procedure
described in Example 6 in 22% yield: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 8.08 (s, 1H), 7.97-7.95 (m, 1H) 7.92-7.90 (m, 1H),
7.84 (s, 1H), 7.54-7.47 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz)
.delta. 153.7, 150.4, 140.7, 131.6, 131.5, 128.8, 128.2, 126.3,
125.5, 117.5; 106.7; MS (Cl) m/z 204.1 (M+1), HPLC retention
time=5.17 min.
EXAMPLE 12
2-(1,4-DIAZA-BICYCLO[3.2.2]NON-4-YL)-1-OXA-3-AZA-CYCLOPENTA[B]NAPHTHALENE
[0142] The title compound was prepared from
2-chloro-1-oxa-3aza-cyclopenta- [b]naphthalene by the procedure
described in Example 8 in 48% yield: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.85-7.80 (m, 2H), 7.65 (s, 1H), 7.57 (s, 1H),
7.40-7.32 (m, 2H), 4.59-4.58 (m, 1H), 3.97 (t, 2H, J=5.8 Hz),
3.20-3.12 (m, 4H), 3.10-3.00 (m, 2H), 2.21-2.14 (m, 2H), 1.88-1.79
(m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 162.8, 149.2,
144.1, 132.1, 129.5, 127.8, 127.7, 124.5, 123.8, 111.7, 104.6,
57.2, 50.6, 46.5, 44.4, 27.0; MS (Cl) m/z 294.2 (M+1); HPLC,
retention time=3.33 min. The hydrochloride salt was prepared by
diluting in ethyl acetate and adding a solution of 2.5 N HCl in
ethyl acetate: mp>300.degree. C.
EXAMPLE 13
1H-3-OXA-1-AZA-CYCLOPENTA[A]NAPHTHALENE-2-THIONE
[0143] The title compound was prepared from 1-amino-2-naphthol by
the procedure described in Example 3 in 98% yield: .sup.1H NMR
(d4-MeOH, 400 MHz) .delta. 7.93 (d, 1H, J=8.3 Hz), 7.87 (d, 1H,
J=7.9 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.56 (t, 1H, J=8.3 Hz),
7.49-7.43 (m, 2H); MS (Cl) m/z 202.1 (M+1).
EXAMPLE 14
2-CHLORO-3-OXA-1-AZA-CYCLOPENTA[A]NAPHTHALENE
[0144] The title compound was prepared from
3H-1-oxa-3-aza-cyclopenta[b]na- phthalene-2-thione by the procedure
described in Example 6 in 77% yield: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 8.41 (dd, 1H, J=8.3, 0.8 Hz), 7.94 (d, 1H, J=7.9 Hz),
7.79 (d, 1H, J=9.1 Hz), 7.68-7.53 (m, 3H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 149.3, 149.2, 136.9, 131.3, 128.8,
127.7, 126.7, 126.1, 126.0, 122.2, 110.4; MS (Cl) m/z 204.1
(M+1).
EXAMPLE 15
2-(1,4-DIAZA-BICYCLO[3.2.2]NON-4-YL)-3-OXA-1-AZA-CYCLOPENTA[A]NAPHTHALENE
[0145] The title compound was prepared from
2chloro-3-oxa-1-aza-cyclopenta- [a]naphthalene by the procedure
described in Example 8 in 33% yield: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 8.33 (d, 1H, J=8.3 Hz), 7.87 (d, 1H, J=8.3 Hz),
7.53-7.40 (m, 4H), 4.60 (s, 1H), 4.01 (t, 2H, J=5.4 Hz), 3.19-3.00
(m, 6H), 2.25-2.15 (m, 2H), 1.88-1.80 (m, 2H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 161.9, 145.0, 138.8, 131.3, 128.6,
125.8, 125.0, 124.7, 122.4, 120.5, 109.9, 57.3, 50.2, 46.6, 44.4,
27.1; MS (Cl) m/z 294.2 (M+1). The hydrochloride salt was prepared
by diluting in ethyl acetate and adding a solution of 2.5 N HCl in
ethyl acetate: mp=167.2.degree. C.
EXAMPLE 16
6-PHENYL-3H-BENZOOXAZOLE-2-THIONE
[0146] The title compound was prepared from 2-amino-5-phenylphenol
(J. Am. Chem. Soc. 1993, 115, 9453) by the procedure described in
Example 3 in 72% yield: .sup.1H NMR (d6DMSO, 400 MHz) .delta. 7.79
(s, 1H), 7.64 (d, 2H, J=7.9 Hz) 7.55 (d 1H, J=8.3 Hz), 743 (t, 2H,
J=7.5 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.27 (d, 1H, J=8.3 Hz); .sup.13C
(d6-DMSO, 100 MHz) .delta. 149.6, 139.9, 137.1, 131.3, 129.7,
128.3, 127.5, 124.5, 111.3, 108.9; MS (Cl) m/z 226.0 (M-1); HPLC
retention time=4.60 min.
EXAMPLE 17
2-CHLORO-4-PHENYLBENZOXAZOLE
[0147] The title compound was prepared from
6-phenyl-3H-benzooxazole-2-thi- one by the procedure described in
Example 6 in 94% yield: mp=85.8.degree. C.; .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.72-7.68 (m, 2H), 7.61-7.58 (m, 3H),
7.49-7.45 (m, 2H), 7.41-7.37 (m, 1H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 152.5, 151.3, 140.6, 140.5, 139.7, 129.2, 128.0,
127.7, 124.8, 119.9, 109.1; MS (Cl) m/z 230.1 (M+1); HPLC retention
time=5.41 min.
EXAMPLE 18
4-(6-PHENYL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0148] The title compound was prepared from
2-chloro-4-phenylbenzoxazole by the procedure described in Example
8 in 33% yield: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.58 (d,
2H, J=7.0 Hz), 7.48 (d, 1H, J=1.2 Hz), 7.44-7.36 (m, 3H), 7.30 (t,
2H, J=7.5 Hz), 4.54-4.52 (m, 1H), 3.94 (t, 2H, J=5.8 Hz), 3.19-3.11
(m, 4H), 3.05-2.98 (m, 2H), 2.20-2.12 (m, 2H), 1.86-1.77 (m, 2H);
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 162.1, 149.6, 143.3,
141.6, 134.2, 129.0, 127.2, 126.9, 123.5, 116.0, 107.5, 57.3, 50.5,
46.6, 44.4, 27.1; MS (Cl) m/z 320.1 (M+1); HPLC retention time=3.55
min. The hydrochloride salt was prepared by diluting in ethyl
acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp=281.3.degree. C.
EXAMPLE 19
4-(5-CHLORO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0149] The title compound was prepared from
5-chloro-2-methylsulfanyl-benz- ooxazole (Chem. Pharm. Bull. 1983,
31, 733) by the procedure described in Example 9 in 40% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.25 (d, 1H, J=2.1 Hz),
7.09 (d, 1H, J=8.3 Hz), 6.91 (dd, 1H, J=8.3, 2.1 Hz), 4.49-4.47 (m,
1H), 3.90 (t, 2H, J=5.8 Hz), 3.20-3.12 (m, 4H), 3.07-2.99 (m, 2H),
2.17-2.09 (m, 2H), 1.85-1.77 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 162.4, 147.5, 145.0, 129.4, 120.2, 116.2, 109.3, 57.0,
50.4, 46.3, 44.0, 26.7; MS (Cl) m/z 278.1 (M+1); HPLC retention
time=3.23 min. The hydrochloride salt was prepared by diluting in
ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp>300.degree. C.
EXAMPLE 20
4-(5-FLUORO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0150] The title compound was prepared from
5-fluoro-2-methylsulfanyl-benz- ooxazole (prepared from
2-amino-4-fluorophenol by the methods described in Example 5 and
Example 7) by the procedure described in Example 9 in 15% yield:
.sup.1H NMR (CDl.sub.3, 400 MHz) .delta. 7.12 (dd, 1H, J=8.7, 4.6
Hz), 7.01 (dd, 1H, J=9.1, 2.5 Hz), 6.70-6.65 (m,1H), 454-4.51 (m,
1H), 3.94 (t, 2H, J=5.8 Hz), 3.24-3.17 (m, 4H), 3.11-3.03 (m, 2H),
2.21-2.14 (m, 2H), 1.90-1.82 (m, 2H); MS:(Cl) m/z 262.1 (M+1); HPLC
retention time=3.08 min. The hydrochloride salt was prepared by
diluting in ethyl acetate and adding a 2.5 N HCl solution in ethyl
acetate: mp>300.degree. C.
EXAMPLE 21
4-(6-NITRO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0151] The title compound was prepared from
2-methylsulfanyl-6-nitro-benzo- oxazole (prepared from
2-amino-5-nitrophenol by the methods described in Example 5 and
Example 7) by the procedure described in Example 9 in 89% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.11 (dd, 1H, J=8.7, 2.1
Hz), 8.05 (d, 1H, J=2.1 Hz), 7.24 (d, 1H, J=8.7 Hz), 4.51 (s, 1H),
3.94 (t, 2H, J=5.8 Hz), 3.18-3.10 (m, 4H), 3.04-2.96 (m, 2H),
2.15-2.09 (m, 2H), 1.87-1.78 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 164.3, 150.6, 148.0, 141.2, 121.7, 114.7, 105.1, 57.0,
51.1, 46.4, 44.7, 26.9; MS (Cl) m/z 289.2 (M+1); HPLC retention
time=3.10 min. The hydrochloride salt was prepared by diluting in
ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp=296.4.degree. C.
EXAMPLE 22
4-(5-IODO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0152] The title compound was prepared from
5-iodo-2-methylsulfanyl-benzoo- xazole (prepared from
4-iodo-2-nitrophenol by the methods described in Examples 4, 5 and
7) by the procedure described in Example 9 in 38% yield: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 7.58 (d, 1H, J=1.2 Hz), 7.23 (dd,
1H, J=8.3, 1.7 Hz), 6.94 (d, 1H, J=8.3 Hz), 4.44-4.42 (m, 1H), 3.85
(t, 2H, J=5.8 Hz), 3.13-3.06 (m, 4H), 2.99-2.92 (m, 2H), 2.12-2.05
(m, 2H), 1.80-1.72 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz)
.delta. 162.0, 148.7, 146.0, 128.9, 124.9, 110.5, 87.2, 57.2, 50.5,
46.5, 44.4, 27.0; MS (Cl) m/z 370.0 (M+1); HPLC retention time=3.44
min. The hydrochloride salt was prepared by diluting in ethyl
acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp>300.degree. C.
EXAMPLE 23
4-(6-BROMO-OXAZOLO[5.4-b]PYRIDIN-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0153] The title compound was prepared from
6-bromo-2-methylsulfanyl-oxazo- lo[5,4-b]pyridine (prepared from
5-bromo-2-hydroxy-3-nitropyridine by the methods described in
Examples 4, 5 and 7) by the procedure described in Example 9 in 64%
yield: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.90 (d, 1H, J=2.1
Hz), 7.59 (d, 1H, J=2.1 Hz), 4.50-4.49 (m, 1H), 3.91 (t, 2H, J=5.8
Hz), 3.18-3.11 (m, 4H), 3.03-2.96 (m, 2H), 2.16-2.08 (m, 2H),
1.85-1.76 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
161.4, 138.8, 125.3, 121.4, 116.7, 116.2, 57.0, 50.6, 46.4, 44.3,
26.8; MS (Cl) m/z323.0 (M+1); HPLC retention time=3.08 min. The
hydrochloride salt was prepared by diluting in ethyl acetate and
adding a 2.5 N HCl solution in ethyl acetate: mp>300.degree.
C.
EXAMPLE 24
4-OXAZOLO[5,4-b]PYRIDIN-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0154] The title compound was prepared from
2-(methylthio)oxazolo[5.4-b]py- ridine (J. Org. Chem. 1995, 60,
5721) by the procedure described in Example 9 in 72% yield: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (dd, 1H, J=5.0, 1.2 Hz),
7.47 (dd, 1H, J=7.5, 1.2 Hz), 7.04 (dd, J=7.5, 5.0 Hz), 4.49-4.47
(m, 1H), 3.89 (t, 2H, J=5.8 Hz), 3.13-3.05 (m, 4H), 3.00-2.92 (m,
2H), 2.13-2.06 (m, 2H), 1.81-1.72 (m, 2H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 160.7, 158.4, 138.6 136.3, 122.7,
120.7, 57.1, 50.4, 46.4, 44.2, 26.9; MS (Cl) m/z 245.2 (M+1). The
hydrochloride salt was prepared by diluting in ethyl acetate and
adding a 2.5 N HCl solution in ethyl acetate: mp>300.degree.
C.
EXAMPLE 25
4-OXAZOLO[5,4-c]PYRIDIN-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0155] The title compound was prepared from
2-(methylthio)oxazolo[5,4-c]py- ridine (J. Org. Chem. 1995, 60,
5721) by the procedure described in Example 9 in 67% yield: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.44 (s, 1H), 8.27 (d, 1H, J=5.0
Hz), 7.19 (d, 1H, J=5.3 Hz), 4.48 (s, 1H), 3.90 (t, 2H, J=5.8 Hz),
3.14-3.07 (m, 4H), 3.00-2.93 (m, 2H), 2.12-2.07 (m, 2H), 1.82-1.74
(m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 163.4, 150.9,
147.5, 145.5, 129.8, 111.6, 62.3, 50.9, 46.4, 44.7, 30.3, 26.9; MS
(Cl) m/z 245.2 (M+1); HPLC retention time=1.28 min. The
hydrochloride salt was prepared by diluting in ethyl acetate and
adding a 2.5 N HCl solution in ethyl acetate: mp>300.degree.
C.
EXAMPLE 26
4-OXAZOLO[4.5-c]PYRIDIN-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0156] The title compound was prepared from
2-(methylthio)oxazolo[4.5-c]py- ridine (J. Org. Chem. 1995, 60,
5721) by the procedure described in Example 9 in 32% yield: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.57 (s, 1H), 8.21 (d, 1H, J=5.4
Hz), 7.16 (d, 1H, J=5.4 Hz), 4.46-4.45 (m, 1H), 3.88 (t, 2H, J=5.8
Hz), 3.14-3.03 (m, 4H), 3.00-2.93 (m, 2H), 2.13-2.06 (m, 2H),
1.82-1.74 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
161.6, 154.3, 142.0, 141.4, 138.0, 104.9, 62.3, 57.1, 50.8, 46.3,
44.6, 30.3, 26.9; MS (Cl) m/z 245.2 (M+1); HPLC retention time=1.28
min. The hydrochloride salt was prepared by diluting in ethyl
acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp=288.5.degree. C.
EXAMPLE 27
4-OXAZOLO[4,5-b]PYRIDIN-2-YL-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0157] The title compound was prepared from
2-(methylthio)oxazolo[4,5-b]py- ridine (J. Org. Chem. 1995, 60,
5721) by the procedure described in Example 9 in 98% yield: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.14 (dd, 1H, J=5.0, 1.2 Hz),
7:34 (dd, 1H, J=7.5, 1.2 Hz), 6.81 (dd, 1H, J=7.8, 5.0 Hz), 4.50
(s, 1H), 3.90 (t, 2H, J.=5.8 Hz), 3.13-3.05 (m, 4H), 2.98-2.91 (m,
2H), 2.13-2.05 (m, 2H), 1.79-1.71 (m, 2H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 163.1, 158.7, 144.7, 141.4, 115.4,
114.8, 57.1, 50.6, 46.4, 46.3,44.4, 30.3, 26.9; MS (Cl) m/z 245.2
(M+1); HPLC retention time=1.38 min. The hydrochloride salt was
prepared by diluting in ethyl acetate and adding a 2.5 N HCl
solution in ethyl acetate: mp>300.degree. C.
EXAMPLE 28
2-AMINO-4-PYRIDIN-3-YL-PHENOL
[0158] Tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol)
was added to a flask containing 4-bromophenol (519 mg, 3.0 mmol),
3-pyridyl boronic acid (553 mg, 4.5 mmol) and sodium carbonate
(1.27 g, 12.0 mmol). The flask was flushed with nitrogen and
ethanol (6 mL) and water (0.6 mL) were added. The mixture was
placed in an oil bath at 80.degree. C. for 16 h. Upon cooling to RT
the mixture was partitioned between water and chloroform. The
aqueous layer was extracted with chloroform (3.times.) and the
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated. The crude residue was purified by chromatography
(Biotage, 40S) eluting with 50% ethyl acetate in hexanes to afford
165 mg (32%) of 4-pyridin-3-yl-phenol as a white solid:
mp=194.6.degree. C., MS (Cl) m/z 172.1 (M+1).
[0159] Nitric acid (60 .mu.L, 1.0 mmol) was added to a solution of
4-pyridin-3-yl-phenol (164 mg, 0.96 mmol) in acetic acid (2.8 mL).
The mixture was heated at 60.degree. C. for 30 min and the solution
turned orange/brown in color. Upon cooling, water was added (3 mL)
and 6 N NaOH (aq) was added until the solution was basic. The
solution was extracted with ethyl acetate (3.times.) and then the
aqueous phase was concentrated. The crude residue was washed with
boiling methanol to afford 90 mg (43%) of
2-nitro4pyridin-3-yl-phenol as an orange solid: mp>300.degree.
C., MS (Cl) m/z 217.1 (M+1).
[0160] A mixture of 2-nitro-4-pyridin-3-yl-phenol (80 mg, 0.37
mmol), 10% Pd--C (8.0 mg), acetic acid (21 .mu.L, 0.37 mmol) in
MeOH (3.7 mL) was hydrogenated at 45 PSI at RT for 16 h. The
mixture was filtered through a pad of celite and concentrate to
afford 70 mg (100%) of the title compound as a brown oil: .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 8.57 (d, 1H, J=1.7 Hz), 8.30 (d,
1H, J=5.0 Hz), 7.75 (dt, 1H, J=7.9, 2.1 Hz), 7.25 (dd, 1H, J=7.9,
5.0 Hz), 6.77-6.69 (m, 2H), 3.94 (br s, 3H); .sup.13C NMR
(CDCl.sub.3, 100 MHz) .delta. 147.0, 146.5, 145.7, 137.6, 135.5,
134.8, 129.3, 124.0, 118.1, 115.4, 114.6; MS (Cl) m/z 187.1 (M+1);
HPLC retention time=1.29 min.
EXAMPLE 29
4-(5-PYRIDIN-3-YL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0161] The title compound was prepared
2-methylsulfanyl-5-pyridin-3-yl-ben- zooxazole (prepared from
2-amino-4-pyridin-3-yl-phenol by the methods described in Examples
5 and 7) by the procedure described in Example 9 in 13% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.83 (d, 1H, J=2.1 Hz),
8.55 (dd, 1H, J=5.0, 1.6 Hz), 7.86-7.83 (m, 1H) 7.52 (d, 1H, J=1.6
Hz), 7.35-7.33 (m 1H), 7.31 (d, 1H, J=8.3 Hz), 7.18 (dd, 1H, J=8.3,
1.6 Hz), 4.45-4.52 (m, 1H), 3.95 (t, 2H, J=5.8 Hz), 3.20-3.12 (m,
4H), 3.07-2.99 (m, 2H), 2.20-2.12 (m, 2H), 1.87-1.79 (m, 2H),
.sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 162.3, 149.1, 148.7,
148.3, 144.7, 137.3, 134.7, 134.4, 123.8, 119.7, 114.7, 109.1,
62.3, 57.2, 50.5, 46.5, 46.4, 44.4, 30.3, 27.0; MS (Cl) m/z 321.1
(M+1). The hydrochloride salt was prepared by diluting in ethyl
acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp>300.degree. C.
EXAMPLE 30
4-(1H-BENZOIMIDAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0162] Di-tert-butyl dicarbonate (600 mg, 2.75 mmol) was added to a
solution of 2-chloroimidazole (381 mg, 2.50 mmol), and sodium
hydroxide (120 mg, 3.0 mmol) in tetrahydrofuran (2.5 mL) and water
(2.5 mL). After 3 h at RT an additional portion of di-tert-butyl
dicarbonate (100 mg, 0.46 mmol) was added and the mixture was
stirred at RT for 16 h. The mixture was extracted with ethyl
acetate (3.times.) and the combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and concentrated to afford 627 mg
(99%) of 2-chloro-benzoimidazole-1-carboxylic acid tert-butyl ester
which was used without further purification: MS (Cl) m/z 253.1
(M+1).
[0163] 2-Chloro-benzoimidazole-1-carboxylic acid tert-butyl ester
(333 mg, 1.32 mmol), 1,4-diazabicyclo[3.2.2]nonane (57%, 195 mg,
0.88 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.031
mmol), racemic-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (58 mg,
0.093 mmol), sodium tert-butoxide (208 mg, 2.17 mmol) and toluene
(1.55 mL) were added to a flame dried round bottom flask purged
with nitrogen. The mixture was placed in an oil bath at 80.degree.
C. for 18 h and then cooled to RT. The mixture was filtered through
a pad of celite and washed with chloroform and methanol. The
filtrate was concentrated and the residue was purified by
chromatography (Biotage, 12M) eluting with 8% methanol in
chloroform with 20 drops of NH.sub.4OH per liter of eluent to
afford 104 mg (34%) of
2-(1,4-diaza-bicydo[3.2.2]non-yl)-benzoimidazole-1-carboxylic acid
tert-butyl ester MS (Cl) m/z 343.1 (M+1).
[0164] 1 N Hydrochloric acid (3 mL, in methanol) was added to of
2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoimidazole-1-carboxylic
add tert-butyl ester (104 mg, 0.304 mmol). The mixture was stirred
at RT for 18 h and concentrated. The residue was diluted with 1 N
hydrochloric acid (3 mL, aq.) and extracted with ethyl acetate
(3.times.). The aqueous layer was treated with 6 N sodium hydroxide
(3 mL, aq.) and extracted with chloroform (6.times.). The combined
organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated to afford 50 mg (68%) of the title compound: .sup.1H
NMR (CD.sub.3OD, 400 MHz) .delta. 7.19 (dd, 2H, J=5.8 Hz, 3.3 Hz),
6.95 (dd, 2H, J=5.8, 2.9 Hz), 4.98 (br s, 1H), 4.27-4.24 (m, 1H),
3.83 (t, 2H, J=5.8 Hz), 3.09-2.91 (m, 6H), 2.16-2.08 (m, 2H),
1.87-1.78 (m, 2H); MS (Cl) m/z 243.3 (M+1H). The hydrochloride salt
was prepared by diluting in ethyl acetate and adding a 2.5 N HCl
solution in ethyl acetate: mp>300.degree. C.
EXAMPLE 31
4-(4-NITRO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0165] The title compound was prepared from
2-methylsulfanyl-4-nitro-benzo- oxazole (prepared from
2-amino-3-nitrophenol by the methods described in Example 5 and
Example 7) by the procedure described in Example 9 in 79% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (dd, 1H, J=8.7, 0.8
Hz), 7.36 (dd, 1H, J=7.5, 0.8 Hz), 6.92 (t, 1H, J=8.3 Hz), 4.51 (s,
1H), 3.93-3.91 (m, 2H), 3.06-2.99 (m, 4H), 2.94-2.87 (m, 2H),
2.07-2.01 (m, 2H), 1.83-1.74 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 163.9, 151.0, 140.3, 133.5, 120.2, 119.2, 113.9, 56.3,
50.6, 45.9, 44.1, 26.3; MS (Cl) m/z 289.2 (M+1); HPLC retention
time=3.02 min. The hydrochloride salt was prepared by diluting in
ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp=232.1.degree. C.
EXAMPLE 32
4-(5-NITRO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0166] The title compound was prepared from
2-methylsulfanyl-5-nitro-benzo- oxazole (prepared from
2-amino-4-nitrophenol by the methods described in Example 5 and
Example 7) by the procedure described in Example 9 in 36% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (d, 1H, J=2.1 Hz),
7.97 (dd, 1H, J=8.7, 2.1 Hz), 7.28 (d, 1H, J=8.7 Hz), 4.56-4.55 (m,
1H), 3.97 (t, 2H, J=5.8 Hz), 3.23-3.16 (m, 4H), 3.08-3.01 (m, 2H),
2.23-2.15 (m, 2H), 1.94-1.85 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 163.1, 152.8, 145.2, 144.3, 117.2, 111.7, 108.5, 56.4,
50.5, 45.9, 43.8, 26.3; MS (Cl) m/z 289.2 (M+1);, HPLC retention
time=3.11 min. The hydrochloride salt was prepared by diluting in
ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp=240.2.degree. C.
EXAMPLE 33
4-(5-METHYL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0167] The title compound was prepared from
5-methyl-2-methylsulfanyl-benz- ooxazole (prepared from
2-amino-4-methylphenol by the methods described in Example 5 and
Example 7) by the procedure described in Example 9 in 4% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.14 (s, 1H), 7.10 (d,
1H, J=7.9 Hz), 6.80 (dd, 1H, J=7.9, 0.8 Hz), 4.55-4.53 (m, 1H),
3.95 (t, 2H, J=5.8 Hz), 3.24-3.17 (m, 4H), 3.10-3.03 (m, 2H), 2.38
(s, 3H), 2.22-2.15 (m, 2H), 1.89-1.81 (m, 2H); MS (Cl) m/z 258.2
(M+1). The hydrochloride salt was prepared by diluting in ethyl
acetate and adding a 2.5 N HCl solution in ethyl acetate:
mp=220.2.degree. C.
EXAMPLE 34
4-(6-METHYL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0168] The title compound was prepared from
6-methyl-2-methylsulfanyl-benz- ooxazole (prepared from
2-amino-5-methylphenol by the methods described in Example 5 and
Example 7) by the procedure described in Example 9 in 2% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.21 (d, 1H, J=7.9 Hz),
7.06 (s, 1H), 6.96 (d, 1H, J=8.3 Hz), 4.55-4.52 (m, 1H), 3.94 (t,
2H, J=5.8 Hz), 3.23-3.15 (m, 4H), 3.09-3.01(m 2) 2.39 (s, 3H),
2.22-2.14 (m, 2H), 1.89-1.80 (m, 2H); MS (Cl) m/z 258.2 (M+1). The
hydrochloride salt was prepared by diluting in ethyl acetate and
adding a 2.5 N HCl solution in ethyl acetate.
EXAMPLE 35
4-(5-METHYL-OXAZOLO[4,5-b]PYRIDIN-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0169] The title compound was prepared from
5-methyl-2-methylsulfanyl-oxaz- olo[4,5-b]pyridine (prepared from
6-methyl-2-nitro-pyridin-3-ol by the methods described in Examples
4, 5 and 7) by the procedure described in Example 9 in 67% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.22 (d, 1H, J=7.9 Hz),
6.65 (d, 1H, J=7.9 Hz), 4.49 (s, 1H), 3.89 (t, 2H, J=5.8 Hz),
3.13-3.05 (m, 4H), 2.99-2.90 (m, 2H), 2.47 (s, 3H), 2.13-2.06 (m,
2H), 1.78-1.70 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta.
163.3, 158.2, 153.5, 139.8, 114.9, 114.3, 57.1, 50.5, 46.4, 44.3,
26.9, 24.1; MS (Cl) m/z 259.2 (M+1); HPLC retention time=2.08 min.
The hydrochloride salt was prepared by diluting in ethyl acetate
and adding a 2.5 N HCl solution in ethyl acetate: mp=287.5.degree.
C.
EXAMPLE 36
4-(6-CHLORO-5-NITRO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0170] The title compound was prepared from
6-chloro-2-methylsulfanyl-5-ni- tro-benzooxazole (prepared from
2-amino-5-chloro-4-nitrophenol by the methods described in Example
5 and Example 7) by the procedure described in Example 9 in 74%
yield: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (d, 1H, J=2.1
Hz), 7.95 (d, 1H, J=2.1 Hz), 4.56-4.54 (m, 1H), 3.97 (t, 2H, J=5.8
Hz), 3.23-3.12 (m, 4H), 3.08-3.01 (m, 2H), 2.20-2.14 (m, 2H),
1.91-1.83 (m, 2H); MS (Cl) m/z 323.1 (M+1). The hydrochloride salt
was prepared by diluting in ethyl acetate and adding a 2.5 N HCl
solution in ethyl acetate: mp=242.3.degree. C.
EXAMPLE 37
4-(5,7-DICHLORO-BENXOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0171] The title compound was prepared from
5,7-dichloro-2-methylsulfanyl-- benzooxazole (prepared from
2-amino-4,6-dichlorophenol by the methods described in Example 5
and Example 7) by the procedure described in Example 9 in 71%
yield: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.17 (d, 1H, J=1.3
Hz), 6.98 (d, 1H, J=1.3 Hz), 4.57 (s, 1H), 3.99 (t, 2H, J=5.8 Hz),
3.30-3.23 (m, 4H), 3.15-3.08 (m, 2H), 2.24-2.17 (m, 2H), 1.95-1.86
(m, 2H); MS (Cl) m/z 312.1 (M+1). The hydrochloride salt was
prepared by diluting in ethyl acetate and adding a 2,5 N HCl
solution in ethyl acetate: mp=251.2 .degree. C.
EXAMPLE 38
4-(5-CHLORO-6-NITRO-BENZOOXAZOL-2-YL)-1,4-DIAZABICYCLO[3.2.2]NONANE
[0172] The title compound was prepared
5-chloro-2-methylsulfanyl-6-nitro-b- enzooxazole (prepared from
2-amino-4-chloro-5-nitrophenol by the methods described in Example
5 and Example 7) by the procedure described in Example 9 in 30%
yield: MS(Cl) m/z 323.1 (M+1). The hydrochloride salt was prepared
by diluting in ethyl acetate and adding a 2.5 N HCl solution in
ethyl acetate: mp>300.degree. C.
EXAMPLE 39
4-(5-AMINO-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0173] 10% Palladium on carbon (300 mg) was added to a solution of
4-(5-nitro-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (288
mg, 1 mmol, prepared as in Example 21) in ethanol (5 mL) and
subjected to hydrogen gas at 50 PSI at RT for a period of 16 h. The
reaction mixture was diluted with ethanol (20 mL) and filtered
through a pad of celite. Concentration in vacuo gave 209 mg of the
title compound as a brown oil: .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta. 7.06 (d, 1H, J=8.3 Hz), 6.75 (d, 1H, J=1.3 Hz), 6.50 (dd,
1H, J=8.3, 1.3 Hz), 4.56 (br s, 1H), 4.08 (br s, 2H), 3.62-3.47 (m,
6H), 2.34-2.31 (m, 2H), 2.20-2.16 (m, 2H); MS (Cl) m/z 259.2
(M+1).
EXAMPLE 40
BENZYL-[2-(1,4-DIAZA-BICYCLO[3.2.2]NON-4-YL)-BENZOOXAZOL-5-YL]-AMINE
[0174] Sodium triacetoxyborohydride (118 mg, 0.56 mmol) was added
to a solution of
4-(5-amino-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (52 mg,
0.20 mmol, prepared as in Example 39) and benzaldehyde (21 .mu.L,
0.204 mmol) in 1,2-dichloroethane. The resulting mixture was
allowed to stir at RT for a period of 3 h. at which time 2 mL of 1
N NaOH solution was added. The aqueous layer was extracted with
CHCl.sub.3 (3.times.) and the combined organic layers were washed
with water and brine and then dried (Na.sub.2SO.sub.4), filtered
and concentrated. The crude residue was purified by chromatography
(Biotage, 25M) eluting with 6% MeOH in CHCl.sub.3 containing 1 mL
of NH.sub.4OH per L of eluent to give 37 mg of the title compound
as an oil: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.37-7.29 (m,
3H), 7.25-7.22 (m, 2H), 7.00 (d, 1H, J=8.7 Hz), 6.64 (d, 1H, J=2.1
Hz), 6.27 (dd, 1H, J=8.7, 2.1 Hz), 4.47-4.45 (m, 1H), 4.30 (s, 2H),
3.87 (t, 2H, J=5.8 Hz), 3.16-3.09 (m, 4H), 3.01-2.96 (m, 2H),
2.15-2.08 (m, 2H), 1.81-1.73 (m, 2H): .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 146.0, 145.1, 142.0, 139.8, 128.8, 127.7, 127.3,
108.8, 106.0, 100.6, 57.3, 50.1, 49.4, 46.5, 44.1, 27.0; MS (Cl)
m/z 349.2 (M+1).
EXAMPLE 41
[2-(1,4-DIAZA-BICYCLO[3.2.2]NON-4-YL)-BENZOOXAZOL-5-YL]-(3-PHENYL-ALLYL)-A-
MINE
[0175] The title compound was prepared according to the procedure
in Example 40 using trans-cinnamaldehyde in 42% yield: MS (Cl) m/z
375.2 (M+1).
EXAMPLE 42
[2-(1,4-DIAZA-BICYCLO[3.2.2]NON-4-YL)-BENZOOXAZOL-5-YL]-PYRIDIN-3-YLMETHYL-
-AMINE
[0176] The title compound was prepared according to the procedure
in Example 40 using 3-pyridinecarboxaldehyde in 52% yield: MS (Cl)
m/z 350.2 (M+1).
EXAMPLE 43
DIBENZYL-[2-(1,4-DIAZA-BICYCLO[3.2.2]NON-4-YL)-BENZOOXAZOL-5-YL]-AMINE
[0177] The title compound was prepared according to the procedure
in Example 40 using 2.2 equivalents of benzaldehyde in 10% yield:
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.37-7.20 (m, 10H), 7.01
(d, 1H, J=8.7 Hz), 6.76 (d, 1H, J=2.1 Hz), 6.39 (dd, 1H, J=8.7, 2.5
Hz), 4.63 (s, 4H), 4.50 (br s, 1H), 3.91-3.89 (m, 2H), 3.20-3.10
(m, 4H), 3.05-2.95 (m, 2H), 2.20-2.10 (m, 2H), 1.90-1.80 (m, 2H);
MS (Cl) m/z 439.2 (M+1).
EXAMPLE 44
4-(5-m-TOLYL-BENZOOXAZOL-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0178] Et.sub.3N (5 .mu.L) was added to a solution of palladium
(II) acetate (0.7 mg, 3.1 .mu.mol) and
2-(N,N-dimethylamino)-2'-dicyclohexylph- osphinobiphenyl (1.8 mg,
4.65 .mu.mol) in 1,2-dimethoxyethane (0.5 mL) under a nitrogen
atmosphere at RT. 4-(5-Bromo-benzooxazol-2-yl)-1,4-diaza-
-bicyclo[3.2.2]nonane (50 mg, 0.155 mmol, prepared in example 9),
m-tolylboronic acid (32 mg, 0.233 mmol) and CsF (70 mg, 0.465 mmol)
were added to the solution and the mixture was heated in an oil
bath (temp=80.degree. C.) for a period of 16 h. The reaction
mixture was cooled to RT, filtered through a pad of celite and
concentrated in vacuo. The crude residue was purified by
chromatography (Biotage, 12L) eluting with 4% MeOH in CHCl.sub.3
with 1 mL of NH.sub.4OH per L to give 39 mg (75%) of the title
compound as a film: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.55
(d, 1H, J=1.7 Hz), 7.40-7.38 (m, 2H), 7.33-7.26 (m, 2H), 7.22-7.19
(m, 1H), 7.14 (d, 1H, J=7.4 Hz), 4.54-4.52 (m, 1H), 3.94 (t, 2H,
J=5.8 Hz), 3.19-3.12 (m, 4H), 3.06-2.99 (m, 2H), 2.41 (s, 3H),
2.20-2.13 (m, 2H), 1.86-1.78 (m, 2H); .sup.13C NMR (CDCl.sub.3, 100
MHz) .delta. 162.2, 148.6, 144.3, 141.9, 138.5, 138.0, 128.9,
128.4, 127.8, 124.6, 119.8, 114.8, 108.7, 57.3, 50.4, 46.5, 44.4,
27.0, 21.8; MS (Cl) m/z 334,1 (M+1).
EXAMPLE 45
4-(6-PHENYL-OXAZOLO[5,4-b]PYRIDIN-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0179] The title compound was prepared according to the procedure
in Example 44 using phenylboronic acid and
4-(6-bromo-oxazolo[5,4-b]pyridin--
2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 23) in
50% yield as a colorless oil: .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.10 (d, 1H, J=2.1 Hz), 7.72 (d, 1H, J=2.1 Hz), 7.57-7.55
(m, 2H), 7.47-7.44 (m, 2H), 7.39-7.36 (m, 1H), 4.58 (br s, 1H),
3.98 (t, 2H, J=5.8 Hz), 3.22-3.14 (m, 4H), 3.11-3.01 (m, 2H),
2.22-2.15 (m, 2H), 1.89-1.82 (m, 2H); MS (Cl) m/z 321.2 (M+1).
EXAMPLE 46
4-[5-(4-TRIFLUOROMETHYL-PHENYL)-BENZOOXAZOL-2-YL]-1,4-DIAZA-BICYCLO[3.2.2]-
NONANE
[0180] The title compound was prepared according to the procedure
in Example 44 using 4-trifluoromethyl-phenylboronic acid and
4-(5-bromo-benzooxazol-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane in 54%
yield: MS (Cl) m/z 388.4 (M+1).
EXAMPLE 47
4-(6-BROMO-OXAZOLO[4.5-b]PYRIDIN-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0181] Bromine (0.12 mL, 2.29 mmol) was added to a solution of
4-oxazolo[4,5-b]pyridin-2-yl-1,4-diaza-bicyclo[3.2.2]nonane (560
mg, 2.29 mmol, prepared in Example 27) and sodium acetate (2.26 g,
27.5 mmol) in water (12 mL) and acetic acid (12 mL). The resulting
mixture was heated to reflux for 2 h. The mixture was cooled and
extracted with ethyl acetate (3.times.). The combined organic
layers were washed with water (2.times.) and brine (1.times.) and
dried over sodium sulfate, filtered and concentrated. The crude
residue was purified by chromatography (Biotage, 25M) using a
gradient elution from 4% MeOH/CHCl.sub.3 containing 0.1% NH.sub.4OH
to 8% MeOH/CHCl.sub.3 containing 0.1% NH.sub.4OH giving 578 mg
(78%) of the title compound as an oil:
[0182] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.23 (d, 1 H,
J=1.7 Hz), 7.50 (d, 1H, J=1.7 Hz), 4.51 (br s, 1H), 3.92 (br s,
2H), 3.16-3.04 (m, 4H), 3.02-2.94 (m, 2H), 2.17-2.01 (m, 2H),
1.83-1.74 (m, 2H); MS (Cl) m/z 325.0/323.0 (M+1).
EXAMPLE 48
4-(6-PHENYL-OXAZOLO[4,5-b]PYRIDIN-2-YL)-1,4-DIAZA-BICYCLO[3.2.2]NONANE
[0183] The title compound was prepared according to the procedure
detailed in Example 44 using phenyl boronic acid and
4-(6-bromo-oxazolo[4,5-b]pyri-
din-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 47)
in 27% yield: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.48 (d,
1H, J=2.1 Hz), 7.62 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.43
(m, 2H), 7.40-7.34 (m, 1H), 4.62 (br s, 1H), 4.00 (t, 2H, J=5.8
Hz), 3.20-3.15 (m, 4H), 3.08-3.01 (m, 2H), 2.19-2.08 (m, 2H),
1.90-1.81 (m, 2H); MS (Cl) m/z 321.2 (M+1).
* * * * *