U.S. patent application number 12/940449 was filed with the patent office on 2011-06-09 for nicotinic acetylcholine receptor ligands 101.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Hui-Fang Chang, Christopher Holmquist, Eifion Phillips, Timothy Piser, Thomas Simpson, Rebecca Urbanek, James Woods, Hui Xiong.
Application Number | 20110136804 12/940449 |
Document ID | / |
Family ID | 38694158 |
Filed Date | 2011-06-09 |
United States Patent
Application |
20110136804 |
Kind Code |
A1 |
Chang; Hui-Fang ; et
al. |
June 9, 2011 |
Nicotinic Acetylcholine Receptor Ligands 101
Abstract
Nicotinic acetylcholine receptor ligands of Formula I
##STR00001## wherein X, n, R.sup.1 and R.sup.2 are as described in
the specification, diastereoisomers, enantiomers,
pharmaceutically-acceptable salts, methods of making,
pharmaceutical compositions containing, and methods for using the
same.
Inventors: |
Chang; Hui-Fang;
(Wilmington, DE) ; Holmquist; Christopher;
(Wilmington, DE) ; Phillips; Eifion; (Boothwyn,
PA) ; Piser; Timothy; (Wilmington, DE) ;
Simpson; Thomas; (Wilmington, DE) ; Urbanek;
Rebecca; (Wilmington, DE) ; Woods; James;
(Wilmington, DE) ; Xiong; Hui; (Wilmington,
DE) |
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
38694158 |
Appl. No.: |
12/940449 |
Filed: |
November 5, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11749820 |
May 17, 2007 |
7842803 |
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12940449 |
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60747476 |
May 17, 2006 |
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60824975 |
Sep 8, 2006 |
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Current U.S.
Class: |
514/233.8 ;
514/278; 544/70; 546/18 |
Current CPC
Class: |
A61P 25/04 20180101;
A61P 25/30 20180101; C07D 491/22 20130101; A61P 25/24 20180101;
A61P 25/34 20180101; A61P 25/16 20180101; A61P 1/04 20180101; A61P
43/00 20180101; A61P 25/28 20180101; A61P 25/00 20180101; A61P
25/18 20180101; A61P 25/20 20180101; A61P 25/22 20180101 |
Class at
Publication: |
514/233.8 ;
546/18; 514/278; 544/70 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 471/22 20060101 C07D471/22; A61K 31/438 20060101
A61K031/438; A61P 25/18 20060101 A61P025/18; A61P 25/22 20060101
A61P025/22; A61P 25/24 20060101 A61P025/24; A61P 25/28 20060101
A61P025/28; A61P 25/16 20060101 A61P025/16; A61P 25/34 20060101
A61P025/34 |
Claims
1. A compound in accord with Formula I: ##STR00038## wherein: X is
independently selected at each occurrence from CH, O, S, N or NH
and at least one X is selected from O, S, N or NH and not more than
one X is O or S; n is 0, 1, 2, or 3, and R.sup.1 and R.sup.2 are
independently selected from hydrogen, --C.sub.1-6alkyl,
--C.sub.3-7cycloalkyl, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl,
--CF.sub.3, --CONR.sup.3R.sup.4, --CH.sub.2NR.sup.3R.sup.4 or
--CH.sub.2OR.sup.3; or, R.sup.1 and R.sup.2 together with the
nitrogen to which they are attached form a 5- or 6-membered
heteroaromatic ring having as ring atoms 1, 2 or 3 heteroatoms
selected from nitrogen, oxygen and sulfur, or a 5- or 6-membered
heterocyclic ring having as ring atoms 1, 2 or 3 heteroatoms
selected from nitrogen, oxygen and sulfur; R.sup.3 and R.sup.4 are
independently selected at each occurrence from hydrogen or
--C.sub.1-4alkyl, and where any alkyl, cycloalkyl, alkenyl or
alkynyl moiety may be substituted with 1, 2, 3 or more halogen,
--OH or .dbd.O moieties as chemically feasible, or a stereoisomer,
enantiomer, in vivo-hydrolysable precursor or
pharmaceutically-acceptable salt thereof.
2. A compound according to claim 1, wherein the moiety ##STR00039##
is selected from moieties of Formulae II, III, IV, V or VI
##STR00040## or a stereoisomer, enantiomer, in vivo-hydrolysable
precursor or pharmaceutically-acceptable salt thereof.
3. A compound according to claim 1, wherein R.sup.1 and R.sup.2 are
independently selected from hydrogen or methyl; or a stereoisomer,
enantiomer, in vivo-hydrolysable precursor or
pharmaceutically-acceptable salt thereof.
4. A compound according to claim 1, wherein n is 1 or 2; or a
stereoisomer, enantiomer, in vivo-hydrolysable precursor or
pharmaceutically-acceptable salt thereof.
5. A compound according to claim 1, wherein R.sup.1 and R.sup.2
together with the nitrogen to which they are attached are selected
from pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; or a
stereoisomer, enantiomer, in vivo-hydrolysable precursor or
pharmaceutically-acceptable salt thereof.
6. A compound according to claim 1, wherein the moiety ##STR00041##
is selected from moieties of Formulae II, III, IV, V or VI,
##STR00042## R.sup.1 and R.sup.2 are independently selected from
hydrogen or methyl, and n is 1 or 2; or a stereoisomer, enantiomer,
in vivo-hydrolysable precursor or pharmaceutically-acceptable salt
thereof.
7. A compound according to claim 1, wherein: the moiety
##STR00043## is a moiety of Formula II or IV, R.sup.1 and R.sup.2
are independently selected from hydrogen or methyl, and n is 1 or
2.
8. A compound according to claim 1, wherein: the moiety
##STR00044## is of Formula II, R.sup.1 and R.sup.2 are
independently selected from hydrogen or methyl, and n is 1 or
2.
9. A compound according to claim 1, wherein: the moiety
##STR00045## is of Formulae I, R.sup.1 and R.sup.2 are
independently selected from hydrogen or methyl, and n is 1 or
2.
10. A compound selected from the group consisting of
N,N-dimethyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-thienyl}methenamine;
N,N-dimethyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-furyl}methenamine;
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-thienyl}methenamine;
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-furyl}methenamine;
N-methyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]oetane-2,2'-furo[2,3-b]p-
yridin]-5'-yl]-2-thienyl}methanamine;
N-methyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]p-
yridin]-5'-yl]-2-furyl}methenamine;
(2R)-5'-[5-(pyrrolidin-1-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]-
octane-2,2'-furo[2,3b]pyridine];
(2R)-5'-[5-(morpholin-4-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]o-
ctane-2,2'-furo[2,3-b]pyridine];
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-furyl}methenamine;
(2R)-5'-[5-(pyrrolidin-1-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]-
octane-2,2'-furo[2,3-b]pyridine];
(2R)-5'-[5-(morpholin-4-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]o-
ctane-2,2'-furo[2,3-b]pyridine];
N-methyl-N-({5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]-
pyridin]-5'-yl]-2-furyl}methyl)cyclopropanamine;
N-methyl-N-({4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]-
pyridin]-5'-yl]-2-furyl}methyl)cyclopropanamine;
1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5-
'-yl]-2-furyl}methenamine;
1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5-
'-yl]-2-thienyl}methenamine, and
1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5-
'-yl]-2-furyl}methenamine; or a stereoisomer, enantiomer, in
vivo-hydrolysable precursor or pharmaceutically-acceptable salt of
any foregoing compound.
11. A method of treatment or prophylaxis of a disease or condition
in which activation of the .alpha.7 nicotinic receptor is
beneficial which method comprises administering a
therapeutically-effective amount of a compound or a
pharmaceutically-acceptable salt thereof according to claim 1 to a
subject suffering from said disease or condition.
12. The method of claim 11, wherein said disease or condition is
anxiety, schizophrenia, mania or manic depression.
13. A method of treatment or prophylaxis of neurological disorders,
psychotic disorders or intellectual impairment disorders, which
comprises administering a therapeutically effective amount of a
compound or a pharmaceutically-acceptable salt thereof according to
claim 1.
14. The method of claim 11, wherein said disorder is Alzheimer's
disease, learning deficit, cognition deficit, attention deficit,
memory loss, Attention Deficit Hyperactivity Disorder, Parkinson's
disease, Huntington's disease, Tourette's syndrome,
neurodegenerative disorders in which there is loss of cholinergic
synapses, jetlag, nicotine addiction, craving, pain, or ulcerative
colitis.
15. A method for inducing the cessation of smoking comprising
administering an effective amount of a compound or a
pharmaceutically-acceptable salt thereof according to claim 1.
16. A pharmaceutical composition comprising a compound or a
pharmaceutically-acceptable salt thereof according to claim 1 and
at least one pharmaceutically-acceptable diluent, lubricant or
carrier.
17. A method of treatment or prophylaxis of a disease or condition
in which activation of the alpha-7 nicotinic receptor is beneficial
which method comprises administering a therapeutically-effective
amount of a pharmaceutical composition according to claim 16 to a
subject suffering from said disease or condition.
18. The method of claim 17, wherein said disease or condition is
anxiety, schizophrenia, mania or manic depression.
19. A method of treatment or prophylaxis of neurological disorders,
psychotic disorders or intellectual impairment disorders, which
comprises administering a therapeutically effective amount of a
pharmaceutical composition according to claim 16.
20. The method of claim 18, wherein said disorder is Alzheimer's
disease, learning deficit, cognition deficit, attention deficit,
memory loss, Attention Deficit Hyperactivity Disorder, Parkinson's
disease, Huntington's disease, Tourette's syndrome,
neurodegenerative disorders in which there is loss of cholinergic
synapses, jetlag, nicotine addiction, craving, pain, or ulcerative
colitis.
21. A method for inducing the cessation of smoking comprising
administering an effective amount of a pharmaceutical composition
according to claim 16.
22-23. (canceled)
Description
FIELD OF THE INVENTION
[0001] This invention relates to furopyridine compounds or
pharmaceutically-acceptable salts thereof, processes for preparing
them, pharmaceutical compositions containing them and their use in
therapy. The invention relates to compounds that bind to nicotinic
acetylcholine receptors (nAChRs) and particularly to compounds that
bind to alpha-7 nicotinic acetylcholine receptors.
BACKGROUND OF THE INVENTION
[0002] Schizophrenia, clinical anxiety and depression daily affect
many millions of people. These conditions are brain disorders that
have serious and lasting effects on people's lives and impact the
sufferers and their friends and relatives.
[0003] People with schizophrenia often have trouble thinking
clearly or making decisions. They may have a hard time telling real
life from fantasy. They may have so-called positive symptoms such
as delusions or hallucinations which they experience but which do
not reflect reality, and see or believe things that are not real;
or they may have negative symptoms and lack behaviors or feelings
that normal people have, avoid social contact and be emotionally
withdrawn. Often they start to do things, but not follow through
and take no pleasure or interest in life; they may be confused in
thinking and speech and act in ways that do not make sense.
[0004] People who have generalized anxiety disorder (GAD) worry
excessively and uncontrollably about everyday things. This constant
worry affects daily functioning and physical symptoms can include
sweating, nausea, gastrointestinal discomfort or diarrhea.
Sufferers tend to be irritable and complain about feeling on edge,
are easily tired and have trouble sleeping. GAD can occur with
other anxiety disorders, depressive disorders, or substance abuse.
The intensity, duration and frequency of worrying varies but is
disproportionate to the issue and interferes with the sufferer's
performance of tasks and ability to concentrate.
[0005] Depressive disorder is an illness that involves the body,
mood, and thoughts. It affects the way a person eats and sleeps,
the way they feel about themselves, and the way they think about
things. People with a depressive illness cannot merely "pull
themselves together" and get better. Without treatment, symptoms
can last for weeks, months, and even years. Major depression
interferes with a person's ability to work, study, sleep, eat, and
enjoy life. A disabling episode of depression may occur only once
but more commonly occurs several times in a lifetime. A less severe
type of depression, termed dysthymia, involves long-term, chronic
symptoms that do not disable, but keep one from functioning well or
from feeling good. Many people with dysthymia also experience major
depressive episodes at some time in their lives. Bipolar disorder
is yet another type of depression that is also called
manic-depressive illness. It is not as prevalent as other forms of
depressive disorders and bipolar disorder is characterized by
cycling mood changes that swing between manic highs and depressive
lows. Sometimes the mood switches are dramatic and rapid, but most
often they are gradual. When in the depressed phase, a person can
have any or all of the symptoms of a depressive disorder. When in
the manic phase, a person may be overactive, overtalkative, and
have a great deal of energy. Manic persons often think differently
and their judgment and social behavior changes in ways that cause
serious problems and embarrassment; they may feel elated, have
grand schemes, make unwise business decisions and indulge in
romantic sprees. Untreated mania can also evolve into a psychotic
state.
[0006] Schizophrenia, clinical anxiety and depression are brain
disorders thought to arise from the overactivity, underactivity or
imbalanced activity of brain cells. Activities of brain cells and
all thinking and feeling are thought to result from the activities
of different brain messengers interacting with receptors on brain
cells. Acetylcholine is one of several messengers by which brain
cell communicate with each other. Acetylcholine interacts with
numerous kinds of receptors some of which are the nicotinic
acetylcholine receptors that are susceptible to the actions of
nicotine found in tobacco. The use of compounds which bind
nicotinic acetylcholine receptors in the treatment of a range of
disorders including schizophrenia, anxiety and depression,
Alzheimer's disease, cognitive or attention disorders, Tourette's
syndrome, and Parkinson's disease has been discussed in McDonald et
al. (1995) "Nicotinic Acetylcholine Receptors: Molecular Biology,
Chemistry and Pharmacology", Chapter 5 in Annual Reports in
Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc., San
Diego, Calif.; and in Williams et al. (1994) "Neuronal Nicotinic
Acetylcholine Receptors," Drug News & Perspectives, vol. 7, pp.
205-223.
[0007] Various nicotinic acetylcholine receptors are known, but one
of particular interest is the alpha-7 nicotinic acetylcholine
receptor and compounds targeting the alpha-7 receptor are thought
to be particularly beneficial for treating schizophrenia, anxiety
and depression.
DESCRIPTION OF THE INVENTION
[0008] This invention concerns nicotinic acetylcholine
receptor-active compounds according to Formula I:
##STR00002##
wherein:
[0009] X is independently selected at each occurrence from CH, O,
S, N or NH and at least one X is selected from O, S, N or NH and
not more than one X is O or S;
[0010] n is 0, 1, 2, or 3, and
[0011] R.sup.1 and R.sup.2 are independently selected at each
occurrence from hydrogen, --C.sub.1-6alkyl, --C.sub.3-7cycloalkyl,
--C.sub.2-6alkenyl, --CF.sub.3, --CONR.sup.3R.sup.4,
--CH.sub.2NR.sup.3R.sup.4 or --CH.sub.2OR.sup.3;
[0012] or, R.sup.1 and R.sup.2 together with the nitrogen to which
they are attached form a 5- or 6-membered heteroaromatic ring
having as ring atoms 1, 2 or 3 heteroatoms selected from nitrogen,
oxygen and sulfur, or a 5- or 6-membered heterocyclic ring having
as ring atoms 1, 2 or 3 heteroatoms selected from nitrogen, oxygen
and sulfur;
[0013] where R.sup.3 and R.sup.4 are independently selected at each
occurrence from hydrogen or --C.sub.1-4alkyl, and
[0014] where any alkyl, cycloalkyl, alkenyl or alkynyl moiety may
be substituted with 1, 2, 3 or more halogen, --OH or .dbd.O
moieties as chemically feasible.
[0015] The invention also encompasses stereoisomers, enantiomers,
in vivo-hydrolysable precursors and pharmaceutically-acceptable
salts of compounds of Formula I, pharmaceutical compositions and
formulations containing them, methods of using them to treat
diseases and conditions either alone or in combination with other
therapeutically-active compounds or substances, processes and
intermediates used to prepare them, uses of them as medicaments,
uses of them in the manufacture of medicaments and uses of them for
diagnostic and analytic purposes. Compounds described herein
selectively bind to alpha-7 nicotinic acetylcholine receptors and
thus are particularly useful for treating schizophrenia, anxiety
and depression.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Compounds are those according to Formula I:
##STR00003##
wherein:
[0017] X is independently selected at each occurrence from CH, O,
S, N or NH and at least one X is selected from O, S, N or NH and
not more than one X is O or S;
[0018] n is 0, 1, 2, or 3, and
[0019] R.sup.1 and R.sup.2 are independently selected at each
occurrence from hydrogen, --C.sub.1-6alkyl, --C.sub.3-7cycloalkyl,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --CF.sub.3,
--CONR.sup.3R.sup.4, --CH.sub.2NR.sup.3R.sup.4 or
--CH.sub.2OR.sup.3;
[0020] or, R.sup.1 and R.sup.2 together with the nitrogen to which
they are attached form a 5- or 6-membered heteroaromatic ring
having as ring atoms 1, 2 or 3 heteroatoms selected from nitrogen,
oxygen and sulfur, or a 5- or 6-membered heterocyclic ring having
as ring atoms 1, 2 or 3 heteroatoms selected from nitrogen, oxygen
and sulfur;
[0021] R.sup.3 and R.sup.4 are independently selected at each
occurrence from hydrogen or --C.sub.1-4alkyl, and
[0022] where any alkyl, cycloalkyl, alkenyl or alkynyl moiety may
be substituted with 1, 2, 3 or more halogen, --OH or .dbd.O
moieties as chemically feasible;
[0023] stereoisomers, enantiomers, in vivo-hydrolysable precursors
and pharmaceutically-acceptable salts thereof.
[0024] Other compounds are those wherein the moiety
##STR00004##
is selected from moieties of Formulae II, III, IV, V or VI
##STR00005##
[0025] Other compounds are those wherein R.sup.1 and R.sup.2 are
independently selected from hydrogen or methyl.
[0026] Other compounds are those wherein n is 1 or 2.
[0027] Yet other compounds are those wherein R.sup.1 and R.sup.2
together with the nitrogen to which they are attached are
pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
[0028] Still other compounds are those wherein the moiety
##STR00006##
is selected from moieties of Formulae II, III, IV, V or VI,
##STR00007##
[0029] R.sup.1 and R.sup.2 are independently selected from hydrogen
or C.sub.1-6alkyl, and
[0030] n is 1 or 2.
[0031] Particular compounds are those wherein the moiety
##STR00008##
is selected from moieties of Formulae II or IV,
##STR00009##
[0032] R.sup.1 and R.sup.2 are independently selected from hydrogen
or C.sub.1-4alkyl, and
[0033] n is 1 or 2.
[0034] Other particular compounds are those wherein the moiety
##STR00010##
is of Formula II,
##STR00011##
[0036] R.sup.1 and R.sup.2 are independently selected from
hydrogen, methyl or ethyl, and
[0037] n is 1 or 2.
[0038] Particular compounds are those wherein the moiety
##STR00012##
is of Formula IV,
##STR00013##
[0040] R.sup.1 and R.sup.2 are independently selected from
hydrogen, methyl or ethyl, and
[0041] n is 1 or 2.
[0042] Particular compounds are those described herein and
pharmaceutically-acceptable salts thereof.
[0043] Another aspect encompasses compounds according to Formula I
wherein one or more of the atoms is a radioisotope of the same
element. In a particular form of this aspect the compound of
Formula I is labeled with tritium. Such radio-labeled compounds are
synthesized either by incorporating radio-labeled starting
materials or, in the case of tritium, exchange of hydrogen for
tritium by known methods. Known methods include (1) electrophilic
halogenation, followed by reduction of the halogen in the presence
of a tritium source, for example, by hydrogenation with tritium gas
in the presence of a palladium catalyst, or (2) exchange of
hydrogen for tritium performed in the presence of tritium gas and a
suitable organometallic (e.g. palladium) catalyst.
[0044] Compounds labeled with tritium are useful for the discovery
of novel medicinal compounds that bind to and modulate the
activity, by agonism, partial agonism, or antagonism, of the
alpha-7 nicotinic acetylcholine receptor. Such tritium-labeled
compounds may be used in assays that measure the displacement of
such a compounds to assess the binding of ligand that bind to
alpha-7 nicotinic acetylcholine receptors.
[0045] Another aspect relates to compounds according to Formula I
and their use in therapy and to compositions containing them.
[0046] Yet another aspect encompasses the use of compounds
according to Formula I for the therapy of diseases mediated through
the action of nicotinic acetylcholine receptors. A more particular
embodiment of this aspect relates to the use of compounds of
Formula I for the therapy of diseases mediated through the action
of alpha-7 nicotinic acetylcholine receptors.
[0047] Another aspect encompasses a method of treatment or
prophylaxis of diseases or conditions in which activation of the
alpha-7 nicotinic receptor is beneficial which method comprises
administering a therapeutically-effective amount of a compound of
Formula I to a subject suffering from said disease or
condition.
[0048] One embodiment of this aspect is a method of treatment or
prophylaxis, wherein the disorder is anxiety, schizophrenia, mania
or manic depression.
[0049] Another embodiment of this aspect is a method of treatment
or prophylaxis of neurological disorders, psychotic disorders or
intellectual impairment disorders, which comprises administering a
therapeutically effective amount of a compound of Formula I.
[0050] Another embodiment of this aspect is a method of treatment
or prophylaxis, wherein the disorder is Alzheimer's disease,
learning deficit, cognition deficit, attention deficit, memory
loss, or Attention Deficit Hyperactivity Disorder.
[0051] Another embodiment of this aspect is a method of treatment
or prophylaxis, wherein the disorder is Parkinson's disease,
Huntington's disease, Tourette's syndrome, or neurodegenerative
disorders in which there is loss of cholinergic synapses.
[0052] Another embodiment of this aspect is a method of treatment
or prophylaxis of jetlag, nicotine addiction, craving, pain, and
for ulcerative colitis, which comprises administering a
therapeutically effective amount of a compound of Formula I.
[0053] Yet another embodiment of this aspect is a method for
inducing the cessation of smoking that comprises administering an
effective amount of a compound of Formula I.
[0054] Another embodiment of this aspect is a pharmaceutical
composition comprising a compound of the invention and at least one
pharmaceutically-acceptable diluent, lubricant or carrier.
[0055] A further aspect relates to a pharmaceutical composition
useful for treating or preventing a condition or disorder mentioned
herein arising from dysfunction of nicotinic acetylcholine receptor
neurotransmission in a mammal, preferably a human, comprising an
amount of a compound of Formula I, an enantiomer thereof or a
pharmaceutically-acceptable salt thereof, effective in treating or
preventing such disorder or condition, and at least one
pharmaceutically-acceptable additive diluent, lubricant or
carrier.
[0056] Another embodiment of this aspect relates to use of a
pharmaceutical composition of the invention for the treatment,
amelioration or prophylaxis of human diseases or conditions in
which activation of the .alpha.7 nicotinic receptor is
beneficial.
[0057] Another embodiment of this aspect is the use of the
pharmaceutical composition a compound of Formula I for the
treatment or prophylaxis of neurological disorders, psychotic
disorders or intellectual impairment disorders.
[0058] Another embodiment of this aspect of the invention is the
use of the pharmaceutical composition comprising a compound of
Formula I for the treatment or prophylaxis of Alzheimer's disease,
learning deficit, cognition deficit, attention deficit, memory
loss, Attention Deficit Hyperactivity Disorder, anxiety,
schizophrenia, or mania or manic depression, Parkinson's disease,
Huntington's disease, Tourette's syndrome, neurodegenerative
disorders in which there is loss of cholinergic synapse, jetlag,
cessation of smoking, nicotine addiction including that resulting
from exposure to products containing nicotine, craving, pain, and
for ulcerative colitis.
[0059] A further aspect is the use of a compound of Formula I, an
enantiomer thereof or a pharmaceutically-acceptable salt thereof,
in the manufacture of a medicament for the treatment or prophylaxis
of the diseases or conditions mentioned herein.
[0060] Another embodiment of this aspect is the use of a compound
of Formula I in the manufacture of a medicament for the treatment
or prophylaxis of human diseases or conditions in which activation
of the alpha-7 nicotinic receptor is beneficial.
[0061] Another embodiment of this aspect is the use of a compound
of Formula I in the manufacture of a medicament for the treatment
or prophylaxis of neurological disorders, psychotic disorders or
intellectual impairment disorders.
[0062] Another embodiment of this aspect is the use of a compound
of Formula I in the manufacture of a medicament for treatment or
prophylaxis of Alzheimer's disease, learning deficit, cognition
deficit, attention deficit, memory loss or Attention Deficit
Hyperactivity Disorder.
[0063] Another embodiment of this aspect is the use of a compound
of Formula I in the manufacture of a medicament for treatment or
prophylaxis of anxiety, schizophrenia, or mania or manic
depression.
[0064] Another embodiment of this aspect is the use of a compound
of Formula I in the manufacture of a medicament for treatment or
prophylaxis of Parkinson's disease, Huntington's disease,
Tourette's syndrome, or neurodegenerative disorders in which there
is loss of cholinergic synapses.
[0065] Another embodiment of this aspect is the use of a compound
of Formula I in the manufacture of a medicament for the treatment
or prophylaxis of jetlag, pain, or ulcerative colitis.
[0066] Another aspect relates to the use of a compound of Formula I
in the manufacture of a medicament for facilitating the cessation
of smoking or the treatment of nicotine addiction or craving
including that resulting from exposure to products containing
nicotine.
[0067] Another aspect relates to the use of a compound of Formula I
in combination with other therapeutically-active compounds or
substances in pharmaceutical compositions or formulations, methods
to treat diseases and conditions, uses as medicaments and uses in
the manufacture of medicaments. Particular embodiments of this
aspect comprise other therapeutically-active compounds or
substances selected from sedatives, hypnotics, anxiolytics,
antipsychotics, antianxiety agents, tranquilizers, and the
like.
[0068] For the uses, methods, medicaments and pharmaceutical
compositions mentioned herein the amount of compound used and the
dosage administered will, of course, vary with the compound
employed, the mode of administration and the treatment desired.
However, in general, satisfactory results are obtained when the
compounds of Formula I are administered at a daily dosage of from
about 0.1 mg to about 20 mg/kg of animal body weight. Such doses
may be given in divided doses 1 to 4 times a day or in sustained
release form. For man, the total daily dose is in the range of from
5 mg to 1,400 mg, more preferably from 10 mg to 100 mg, and unit
dosage forms suitable for oral administration comprise from 2 mg to
1,400 mg of the compound admixed with a solid or liquid
pharmaceutical carriers, lubricants and diluents.
[0069] The compounds of Formula I, an enantiomer thereof, and
pharmaceutically-acceptable salts thereof, may be used on their own
or in the form of appropriate medicinal preparations for enteral or
parenteral administration. According to a further aspect there is
provided a pharmaceutical composition including preferably less
than 80% and more preferably less than 50% by weight of a compound
of Formula I in admixture with an inert pharmaceutically-acceptable
diluent, lubricant or carrier. Examples of diluents, lubricants and
carriers are: [0070] for tablets and dragees: lactose, starch,
talc, stearic acid; [0071] for capsules: tartaric acid or lactose;
[0072] for injectable solutions: water, alcohols, glycerin,
vegetable oils; [0073] for suppositories: natural or hardened oils
or waxes.
[0074] There is also provided a process for the preparation of such
a pharmaceutical composition which process comprises mixing the
ingredients.
[0075] Compounds described herein are agonists of nicotinic
acetylcholine receptors. While not being limited by theory, it is
believed that agonists of the alpha-7 nicotinic acetylcholine
receptor (nAChR) subtype are useful in the treatment or prophylaxis
of neurological disorders, psychotic disorders and intellectual
impairment disorders. The compounds described herein are indicated
as pharmaceuticals, in particular in the treatment or prophylaxis
of neurological disorders, psychotic disorders and intellectual
impairment disorders. Examples of psychotic disorders include
schizophrenia, mania and manic depression, and anxiety. Examples of
intellectual impairment disorders include Alzheimer's disease,
learning deficit, cognition deficit, attention deficit, memory
loss, and Attention Deficit Hyperactivity Disorder. Compounds
described herein may also be useful as analgesics in the treatment
of pain, chronic pain, and in the treatment or prophylaxis of
Parkinson's disease, Huntington's disease, Tourette's syndrome, and
neurodegenerative disorders in which there is loss of cholinergic
synapses.
[0076] Compounds may further useful for the treatment or
prophylaxis of jetlag, for use in inducing the cessation of
smoking, craving, and for the treatment or prophylaxis of nicotine
addiction including that resulting from exposure to products
containing nicotine.
[0077] It is also believed that compounds described herein are
useful in the treatment and prophylaxis of ulcerative colitis.
[0078] A compound of Formula I or a pharmaceutically acceptable
salt, solvate or in vivo hydrolysable ester thereof, or a
pharmaceutical composition or formulation comprising a compound of
Formula I may be administered concurrently, simultaneously,
sequentially or separately with another pharmaceutically active
compound or compounds selected from the following:
(i) antidepressants such as amitriptyline, amoxapine, bupropion,
citalopram, clomipramine, desipramine, doxepin duloxetine,
elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone,
imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone,
paroxetine, phenelzine, protriptyline, reboxetine, robalzotan,
sertraline, sibutramine, thionisoxetine, tranylcypromaine,
trazodone, trimipramine, venlafaxine and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof; (ii)
atypical antipsychotics including for example quetiapine and
pharmaceutically active isomer(s) and metabolite(s) thereof; (iii)
antipsychotics including for example amisulpride, aripiprazole,
asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine,
chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone,
haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine,
olanzapine, paliperidone, perlapine, perphenazine, phenothiazine,
phenylbutylpiperidine, pimozide, prochlorperazine, risperidone,
sertindole, sulpiride, suproclone, suriclone, thioridazine,
trifluoperazine, trimetozine, valproate, valproic acid, zopiclone,
zotepine, ziprasidone and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof; (iv) anxiolytics including for
example alnespirone, azapirones, benzodiazepines, barbiturates such
as adinazolam, alprazolam, balezepam, bentazepam, bromazepam,
brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide,
cyprazepam, diazepam, diphenhydramine, estazolam, fenobam,
flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam,
meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam,
reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam,
zolazepam and equivalents and pharmaceutically active isomer(s) and
metabolite(s) thereof; (v) anticonvulsants including for example
carbamazepine, valproate, lamotrogine, gabapentin and equivalents
and pharmaceutically active isomer(s) and metabolite(s) thereof;
(vi) Alzheimer's therapies including for example donepezil,
memantine, tacrine and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof; (vii) Parkinson's therapies
including for example deprenyl, L-dopa, Requip, Mirapex, MAOB
inhibitors such as selegine and rasagiline, comP inhibitors such as
Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA
antagonists, Nicotine agonists, Dopamine agonists and inhibitors of
neuronal nitric oxide synthase and equivalents and pharmaceutically
active isomer(s) and metabolite(s) thereof; (viii) migraine
therapies including for example almotriptan, amantadine,
bromocriptine, butalbital, cabergoline, dichloralphenazone,
eletriptan, frovatriptan, lisuride, naratriptan, pergolide,
pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan,
zomitriptan, and equivalents and pharmaceutically active isomer(s)
and metabolite(s) thereof; (ix) stroke therapies including for
example abciximab, activase, NXY-059, citicoline, crobenetine,
desmoteplase, repinotan, traxoprodil and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof; (x)
urinary incontinence therapies including for example darafenacin,
falvoxate, oxybutynin, propiverine, robalzotan, solifenacin,
tolterodine and equivalents and pharmaceutically active isomer(s)
and metabolite(s) thereof; (xi) neuropathic pain therapies
including for example gabapentin, lidoderm, pregablin and
equivalents and pharmaceutically active isomer(s) and metabolite(s)
thereof; (xii) nociceptive pain therapies such as celecoxib,
etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac,
loxoprofen, naproxen, paracetamol and equivalents and
pharmaceutically active isomer(s) and metabolite(s) thereof; (xiii)
insomnia therapies including for example allobarbital, alonimid,
amobarbital, benzoctamine, butabarbital, capuride, chloral,
cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate,
glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin,
mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital,
phenobarbital, propofol, roletamide, triclofos, secobarbital,
zaleplon, zolpidem and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof, or (xiv) mood stabilizers
including for example carbamazepine, divalproex, gabapentin,
lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic
acid, verapamil, and equivalents and pharmaceutically active
isomer(s) and metabolite(s) thereof.
[0079] Such combination products employ the compounds of this
invention within the dosage range described herein and the other
pharmaceutically active compound or compounds within approved
dosage ranges and/or the dosage described in the publication
reference.
[0080] The compounds described herein have the advantage that they
may be less toxic, be more efficacious, be longer acting, have a
broader range of activity, be more potent, produce fewer side
effects, are more easily absorbed or have other useful
pharmacological properties.
[0081] As used herein, unless otherwise indicated, "C.sub.1-6alkyl"
includes C.sub.1-4 alkyl groups but is not limited to methyl,
ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl
moieties, whether alone or part of another group, C.sub.1-4alkyl
groups may be straight-chained or branched, and C.sub.3-4alkyl
groups include cyclic alkyl moieties such as cyclopropyl and
cyclobutyl.
[0082] As used herein, unless otherwise indicated,
"C.sub.2-6alkenyl" includes C.sub.2-4alkenyl but is not limited to
1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.
[0083] As used herein, unless otherwise indicated,
"C.sub.2-6alkynyl" includes C.sub.2-4alkynyl but is not limited to
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and
3-butynyl.
[0084] As used herein, unless otherwise indicated, aryl refers to a
phenyl ring that may have 1, 2 or 3 substituents selected from:
halogen, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
NO.sub.2, and CF.sub.3.
[0085] As used herein, unless otherwise indicated, heteroaryl
refers to a 5- or 6-membered heteroaromatic ring having 1, 2 or 3
heteroatoms selected from nitrogen, oxygen and sulfur, and
heterocyclyl refers to a 5- or 6-membered heterocyclic ring having
1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur,
provided that such heteroaromatic or heterocyclic rings contains at
least one nitrogen, oxygen, or sulfur atom.
[0086] As used herein, unless otherwise indicated, halogen refers
to fluorine, chlorine, bromine, or iodine.
[0087] Where necessary, hydroxy, amino, or other reactive groups
may be protected using a protecting group as described in the
standard text "Protecting groups in Organic Synthesis", 3.sup.rd
Edition (1999) by Greene and Wuts.
[0088] Unless otherwise stated, reactions are conducted under an
inert atmosphere, preferably under a nitrogen atmosphere and are
usually conducted at a pressure of about one to about three
atmospheres, preferably at ambient pressure (about one
atmosphere).
[0089] Compounds and intermediates may be isolated from their
reaction mixtures by standard techniques.
[0090] Acid addition salts of the compounds of Formula I which may
be mentioned include salts of mineral acids, for example the
hydrochloride and hydrobromide salts; and salts formed with organic
acids such as formate, acetate, maleate, benzoate, tartrate, and
fumarate salts.
[0091] Acid addition salts of compounds of Formula I may be formed
by reacting the free base or a salt, enantiomer or protected
derivative thereof, with one or more equivalents of the appropriate
acid. The reaction may be carried out in a solvent or medium in
which the salt is insoluble or in a solvent in which the salt is
soluble, e.g., water, dioxane, ethanol, tetrahydrofuran or diethyl
ether, or a mixture of solvents, which may be removed in vacuum or
by freeze drying. The reaction may be a metathetical process or it
may be carried out on an ion exchange resin.
[0092] The compounds of Formula I may exist in tautomeric or
enantiomeric forms, all of which are included within the scope. The
various optical isomers may be isolated by separation of a racemic
mixture of the compounds using conventional techniques, e.g.
fractional crystallization, or chiral HPLC. Alternatively the
individual enantiomers may be made by reaction of the appropriate
optically active starting materials under reaction conditions that
will not cause racemisation.
Pharmacology
[0093] The pharmacological activity of compounds of the invention
may be measured by using tests such as those set out below:
Assay for Affinity at an .alpha..sub.7 nAChR Receptor by Measuring
the Binding of .sup.125I-.alpha.-bungarotoxin (BTX) Binding to Rat
Hippocampal Membranes.
[0094] Rat brain cell membranes bearing .alpha..sub.7 nAChR
receptors may be prepared by homogenizing hippocampus tissue in 20
volumes of cold homogenization buffer (FIB): mM concentrations of
HB constituents: tris(hydroxymethyl)aminomethane 50; CaCl.sub.2 2;
MgCl.sub.2 1; NaCl 120; KCl 5: pH 7.4). Homogenates are centrifuged
for 5 minutes at 1000.times.g, the supernatant saved and the
pellets re-extracted and centrifuged. Pooled supernatants are
centrifuged for 20 minutes at 12,000.times.g, the pelleted
membranous material is washed, and re-suspended in HB. Membranes
(30-150 .mu.g) are incubated with 3 nM [.sup.125I].alpha.-BTX, 1
mg/mL bovine serum albumin (BSA), together with test compounds in
HB for 2 hours at room temperature with gentle shaking. Membranes
may then be trapped on Whatman glass fiber filters (thickness C or
B) using a Brandel cell harvester and washed 4 times. Pre-treating
the filters for 3 hours with 1% (BSA/0.01% PEI (polyethyleneimine)
in water will yield low filter blanks (0.07% of total counts per
minute). Non-specific binding may be determined by 100 .mu.M
(-)-nicotine. Typically specific binding is about 75%.
Assay for Affinity at Human .alpha..sub.7 nAChR Receptor by the
Binding of .sup.125I-.alpha.-bungarotoxin (BTX) Binding to
Membranes.
[0095] Membranes may be prepared from HEK cells expressing human
.alpha..sub.7 receptors by isolating a 500-40000.times.g membrane
fraction. Such membranes may be used as described for rat brain
membranes to assess the binding of compounds to human .alpha..sub.7
receptors.
Analysis of Binding Data Obtained in .alpha..sub.7 nAChR Receptor
Assays
[0096] IC.sub.50 values and pseudo Hill coefficients (n.sub.H) may
be calculated using the non-linear curve-fitting program ALLFIT
(DeLean A, Munson P J and Rodbard D (1977) Am. J. Physiol.,
235:E97-E102). Saturation curves may be fitted to a one site model,
using the non-linear regression program ENZFITTER (Leatherbarrow,
R. J. (1987)), yielding a Kd value for [.sup.125I]-.alpha.-BTX
binding to rat .alpha.7 nAChR of 1.7 nM. K.sub.i values may be
estimated using the general Cheng-Prusoff equation:
K.sub.i=[IC.sub.50]/((2+([ligand]/K.sub.D).sup.n).sup.1/n-1)
[0097] where a value of n=1 is used whenever n.sub.H<1.5 and a
value of n=2 is used when n.sub.H.gtoreq.1.5. To account for
variability, assays may be performed in triplicate and variability
will typically be .+-.5%. K.sub.i values may be determined using
six to 11 drug concentrations.
[0098] Compounds of the invention expected to have useful
therapeutic activity will be found to have binding affinities
(K.sub.i) of less than 10 .mu.M in .alpha..sub.7 nAChR receptor
assays.
[0099] The compounds of the invention have the advantage that they
may be less toxic, be more efficacious, be longer acting, have a
broader range of activity, be more potent, produce fewer side
effects, are more easily absorbed or have other useful
pharmacological properties.
General Experimental Procedures and Conditions
[0100] Commercial reagents were used without further purification.
Mass spectra were recorded as m/z for the parent molecular ion
unless specified otherwise. Room temperature (rt) refers to
20-25.degree. C.
[0101] Microwave heating was achieved with a Personal Chemistry
Smith Synthesizer or a Personal Chemistry Emrys Optimizer
(monomodal, 2.45 GHz, 300 W max). Supercritical Fluid
Chromatography (SFC) may have been performed as a means of
purification for selected compounds and intermediates.
[0102] LCMS HPLC method was generally performed with an Agilent
Zorbax 5.mu. SB-C8 column 2.1 mm.times.5 cm. Solvents: A=H.sub.2O
with 2% ACN and 0.1% formic acid, B=2% H.sub.2O with 98% ACN and
0.05% formic acid. Gradient: (0% B through 0.5 min, 60% B at 3
min., 95% B at 6 min.).
ABBREVIATIONS USED
[0103] ACN acetonitrile AcOH acetic acid DCE 1,2-dichloroethane DME
1,2-dimethoxyethane ES.sup.+ electrospray EtOAc ethyl acetate EtOH
ethanol Et.sub.2O diethyl ether h hours Hz hertz HPLC high
performance liquid chromatography
LCMS Liquid Chromatography Mass Spectrometry
[0104] MeOH methanol min minutes MS mass spectrometry m/z mass to
charge nBuLi n-butyllithium rt room temperature NMR nuclear
magnetic resonance THF tetrahydrofuran
Methods of Preparation
[0105] Methods that may be used for the synthesis of compounds of
Formula I, include the procedures illustrated in Scheme 1 and
processes analogous to those described in the Examples. In Scheme
1X, n, R.sup.1 and R.sup.2 are as defined for compounds of Formula
I.
##STR00014##
[0106] It will be appreciated by those skilled in the art that
aromatic substituents in the compounds of the invention, or in
intermediates used in the synthesis of compounds of the invention,
may be introduced by employing aromatic substitution reactions,
functional group transformations to modify existing substituents,
or a combination thereof. Such reactions may be effected either
prior to or immediately following the processes mentioned above.
The reagents and reaction conditions for such procedures are known
in the art. Specific examples of procedures which may be employed
include, but are not limited to, electrophilic functionalization of
an aromatic ring, for example by nitration, halogenation, or
acylation; transformation of a nitro group to an amino group, for
example by reduction, such as by catalytic hydrogenation;
acylation, alkylation, sulfonylation of an amino or hydroxyl group;
replacement of an amino group by another functional group by
conversion to an intermediate diazonium salt followed by
nucleophilic or free radical substitution of the diazonium salt; or
replacement of a halogen by another functional group, for example
by nucleophilic or organometallically-catalysed substitution
reactions.
EXAMPLES
Example 1
N,N-dimethyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3--
b]pyridin]-5'-yl]-2-thienyl}methenamine
##STR00015##
[0107] a) {5-[(dimethylamino)methyl]-2-thienyl}boronic acid
##STR00016##
[0109] To a suspension of 5-formyl-2-thiopheneboronic acid (500 mg,
3.2 mmol) in DCE (30 mL) was added dimethylamine hydrochloride (520
mg, 6.3 mmol) followed by triethylamine (0.9 mL, 6.5 mmol). The
reaction mixture was stirred for 10 min before sodium
triacetoxyborohydride (1.36 g, 6.3 mmol) was added in one portion.
After the reaction mixture was stirred at room temperature for 5 h,
it was quenched with 30 mL of MeOH, stirred briefly, then
concentrated under vacuum. Introduction of a
CH.sub.2Cl.sub.2/Et.sub.2O mixture to this residue revealed a
solid, which was filtered and washed with Et.sub.2O. The resulting
organic filtrate was concentrated to a viscous oil, which was used
without further purification.
b) To a solution of {5-[(dimethylamino)methyl]-2-thienyl}boronic
acid (2.23 mmol) in 10 mL of a DME:H.sub.2O:EtOH mixture (7:3:2)
was added
(2R)-5'-bromo-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin-
e] (330 mg, 1.11 mmol). The reaction mixture was stirred for
several minutes until homogeneous, at which point
Pd(PPh.sub.3).sub.2Cl.sub.2 (77 mg, 0.11 mmol) was added followed
by solid Na.sub.2CO.sub.3 (945 mg, 8.92 mmol). The reaction mixture
was purged with N.sub.2 and heated at 65.degree. C. overnight. The
reaction mixture was concentrated by rotary evaporation, then
partitioned between water and CHCl.sub.3. The organic layer was
isolated and the aqueous layer was extracted 4.times.50 mL
CHCl.sub.3. The combined organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated to a viscous oil. The
product was chromatographed through silica gel and eluted using
9.5:0.5 CHCl.sub.3 and 7.0 M ammonia in methanol. The title
compound was further purified by trituration in ether and isolated
as a solid (150 mg). .sup.1HNMR (500 MHz, CD.sub.3OD) .delta.
1.58-1.65 (m, 1H), 1.74-1.83 (m, 2H), 2.04 (bs, 1H), 2.14-2.24 (m,
1H), 2.29 (s, 6H), 2.81-2.87 (m, 2H), 2.92-2.98 (m, 2H), 3.07 (d,
J=16 Hz, 1H), 3.18 (d, J=17 Hz, 1H), 3.28 (d, J=16 Hz, 1H), 3.54
(d, J=17 Hz, 1H), 3.68 (s, 2H), 6.94 (d, J=3.6 Hz, 1H), 7.16 (d,
J=3.6 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H) MS
ES.sup.(+), m/z=356 (M+Na).
Example 2
N,N-dimethyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3--
b]pyridin]-5'-yl]-2-furyl}methenamine
##STR00017##
[0110] a) {5-[(dimethylamino)methyl]-2-furyl}boronic acid
##STR00018##
[0112] To a solution of (5-formyl-2-furyl)boronic acid (50 mg, 0.36
mmol) in DME (1.0 mL) was added a 2.0M solution of dimethylamine in
THF (0.53 mL, 1.0 mmol). The reaction mixture stirred for 5 minutes
before resin bound MP-BH(OAc).sub.3 (2.2 mmol/g, 0.33 g, 0.714
mmol) was added. The reaction mixture was stirred at room
temperature for five hours and an additional 1 equivalent of
dimethylamine in THF was added and stirring continued overnight.
The reaction mixture was filtered through a plug of glass wool and
the resin was washed with DME. The THF/DME filtrate solution
containing the desired compound was used immediately in subsequent
reactions.
b) To a solution of {5-[(dimethylamino)methyl]-2-furyl}boronic acid
(0.25 mmol) in 2.5 mL of a DME:H.sub.2O:EtOH mixture (7:3:2) was
added
(2R)-5'-bromo-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin-
e] (37 mg, 0.12 mmol). The reaction mixture was stirred for several
minutes until homogeneous, at which point
Pd(PPh.sub.3).sub.2Cl.sub.2 (9 mg, 0.012 mmol) was added followed
by solid Na.sub.2CO.sub.3 (53 mg, 0.5 mmol). The reaction mixture
was purged with N.sub.2 and heated at 65.degree. C. for 4.5 h. The
reaction mixture was partitioned between water and CHCl.sub.3. The
organic layer was isolated and the aqueous layer was extracted
2.times.50 mL CHCl.sub.3. The combined organic layer was washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated.
The product was purified by preparative plate chromatography using
9.0:1.0 CHCl.sub.3 and 7.0 M ammonia in methanol as the eluant. The
title compound was isolated as viscous oil (30 mg). .sup.1H NMR
(500 MHz, CD.sub.3OD) .delta. 1.59-1.63 (m, 1H), 1.73-1.82 (m, 2H),
2.04 (bs, 1H), 2.18-2.22 (m, 1H), 2.29 (s, 6H), 2.83-2.86 (m, 2H),
2.92-2.95 (m, 2H), 3.06 (d, J=16 Hz, 1H), 3.18 (d, J=16 Hz, 1H),
3.26 (d, J=16 Hz, 1H), 3.54 (d, J=16 Hz, 1H), 3.68 (s, 2H), 6.38
(d, J=3.2 Hz, 1H), 6.66 (d, J=3.2 Hz, 1H), 7.91 (d, J=2 Hz, 1H),
8.26 (d, J=2 Hz, 1H) MS ES.sup.(+), m/z=340 (M+Na).
[0113] Alternatively,
N,N-dimethyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-furyl}methenamine can be prepared via the
aldehyde by the method given below.
a)
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-
-yl]-2-furaldehyde
##STR00019##
[0115] To a solution of
(2R)-5'-bromo-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin-
e] (6 g, 20.3 mmol) in 400 mL of a DME:H.sub.2O:EtOH mixture
(7:3:2) was added 5-formyl-2-furanboronic acid (5.67 g, 40.5 mmol).
The reaction mixture was purged with N.sub.2 (directly into the
solvent) and stirred for ten minutes until homogeneous. Solid
Na.sub.2CO.sub.3 (8.6 g, 81.0 mmol) was added to the reaction
mixture followed by Pd(PPh.sub.3).sub.2Cl.sub.2 (711 mg, 1.0 mmol).
The reaction mixture was again purged with N.sub.2 for 10 min, then
heated at 65.degree. C. for 6 h. The reaction mixture was stirred
at rt overnight, then concentrated via rotary evaporator. The
resulting residue was diluted with CHCl.sub.3 and filtered through
diatomaceous earth. The CHCl.sub.3 filtrate was concentrated and
the resulting residue was diluted with 1N HCl and extracted with
EtOAc (3.times.150 mL). The acidic aqueous layer was made basic
with the addition of 2N aqueous NaOH (to pH.about.12) and the basic
aqueous solution was extracted with CHCl.sub.3 (3.times.150 mL).
The combined CHCl.sub.3 layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated to a solid (5.79 g,
92% yield). This material was used without further purification.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.46-1.53 (m, 1H),
1.68-1.71 (m, 2H), 2.03-2.04 (m, 1H), 2.22-2.26 (m, 1H), 2.78-2.94
(m, 3H), 2.97 (d, J=14.7 Hz, 1H), 3.00-3.04 (m, 1H), 3.07 (d,
J=16.5 Hz, 1H), 3.40 (d, J=14.7 Hz, 1H), 3.47 (d, J=16.5 Hz, 1H),
6.74 (d, J=3.7 Hz, 1H), 7.30 (d, J=3.7 Hz, 1H), 7.89 (s, 1H), 8.48
(s, 1H), 9.62 (s, 1H) MS ES.sup.+, m/z=311 (M+H.sup.+).
b)
N,N-dimethyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2-
,3-b]pyridin]-5'-yl]-2-furyl}methenamine
[0116] To a solution of
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-y-
l]-2-furaldehyde (5.8 g, 18.7 mmol) in methanol (180 mL) at room
temperature under N.sub.2 was added dimethylamine (18.7 mL of a 2.0
M THF solution, 37.3 mmol). The reaction mixture was stirred for 30
min at rt before AcOH (4.3 mL, 74.7 mmol) was added followed by the
portionwise addition of NaBH.sub.3CN (1.74 g, 28.0 mmol). The
reaction mixture was then stirred at rt for 4 h, then concentrated
via rotary evaporation. The resulting residue was diluted with
saturated aqueous K.sub.2CO.sub.3 and extracted with CHCl.sub.3
(4.times.100 mL). The combined CHCl.sub.3 layer was washed with
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated to a
viscous residue. The product was purified by column chromatography
(SiO.sub.2) using 9.5:0.5 CHCl.sub.3 and 7.0 M ammonia in MeOH to
elute the desired compound.
Example 3
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3--
b]pyridin]-5'-yl]-2-thienyl}methenamine
##STR00020##
[0118] The compound of Example 3 was prepared by a process
analogous to that used for Example 1, as detailed below.
a) 1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine
##STR00021##
[0120] To a solution of 4-bromothiophene-2-carboxyaldehyde (5 g,
26.3 mmol) in EtOH (130 mL) at rt and under N.sub.2 was added the
dimethylamine in THF (20 mL of a 2.0 M solution, 40 mmol) followed
by AcOH (1.9 mL). NaBH.sub.3CN (2.1 g, 34 mmol) was then added in
portions to the reaction mixture over a 5 min period and the
reaction mixture was stirred overnight at rt. The reaction mixture
was diluted with saturated NaHCO.sub.3 and extracted with
CHCl.sub.3 (3.times.50 mL). The combined organic layer was
concentrated and the resulting residue was diluted with 1 N HCl and
washed with CHCl.sub.3. The acidic aqueous layer was then made
basic with the addition of saturated NaHCO.sub.3 and extracted with
CHCl.sub.3 (3.times.50 mL). The combined organic layer was washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated
(86% yield). The product was used without further purification.
.sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 2.26 (s, 6H), 3.65 (s,
2H), 6.92 (apparent s, 1H), 7.31 (d, J=2 Hz, 1H).
b) Diisopropyl {5-[(dimethylamino)methyl]-3-thienyl}boronate
##STR00022##
[0122] To a solution of
1-(4-bromo-2-thienyl)-N,N-dimethylmethanamine (2.8 g, 12.8 mmol) in
THF (130 mL) at -78.degree. C. under N.sub.2 was added
tri-isopropylborate (4.4 mL, 19.2 mmol). The reaction mixture was
stirred briefly before nBuLi (12 mL of a 1.6 M hexane solution) was
added dropwise via syringe. The reaction mixture then stirred for
6.5 h at -78.degree. C. before being concentrated by rotary
evaporation. The resulting white solid was used without further
purification.
c)
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2-
,3-b]pyridin]-5'-yl]-2-thienyl}methenamine
##STR00023##
[0124] To a solution of diisopropyl
{5-[(dimethylamino)methyl]-3-thienyl}boronate (3.6 g, 13 mmol) in
120 mL of a DME:H.sub.2O:EtOH mixture (7:3:2) was added
(2R)-5'-bromo-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin-
e] (2.0 g, 6.75 mmol). The reaction mixture was purged with N.sub.2
and stirred for several min until homogeneous, at which point
Na.sub.2CO.sub.3 (2.9 g, 27 mmol) was added, followed by
Pd(PPh.sub.3).sub.2Cl.sub.2 (236 mg, 0.34 mmol). The reaction
mixture was purged with N.sub.2 for 10 min, then heated at
75.degree. C. for 2 h and at rt overnight. The reaction mixture was
concentrated by rotary evaporation. The resulting residue was
diluted with CHCl.sub.3 and filtered though diatomaceous earth. The
organic filtrate was concentrated and the resulting residue was
diluted with 1 N HCl and extracted with EtOAc (3 times). The acidic
aqueous layer was then made basic with the addition of 2 N NaOH and
extracted with CHCl.sub.3 (4.times.100 mL). The combined organic
layer was washed with brine, dried (NON, filtered and concentrated
to a viscous oil. The product was chomatographed though silica gel
and eluted using 9.5:0.5 CHCl.sub.3 and 7.0 M ammonia in methanol.
The title compound was further purified by trituration in Et.sub.2O
and isolated (1.5 g, 62% yield). .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. 1.58-1.64 (m, 1H), 1.73-1.82 (m, 2H), 2.04 (bs, 1H),
2.18-2.24 (m, 1H), 2.30 (s, 6H), 2.83-2.86 (m, 2H), 2.93-2.98 (m,
2H), 3.06 (d, J=14.6 Hz, 1H), 3.18 (d, J=16.5 Hz, 1H), 3.26 (d,
J=14.6 Hz, 1H), 3.54 (d, J=17 Hz, 1H), 3.71 (s, 2H), 7.28 (s, 1H),
7.50 (s, 1H), 7.88 (s, 1H), 8.17 (s, 1H) MS ES.sup.+, m/z=356
(M+Na.sup.+).
Example 4
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3--
b]pyridin]-5'-yl]-2-furyl}methenamine
##STR00024##
[0126] The compound of Example 4 may be prepared by a process
analogous to that used for Example 2.
Example 5
N-methyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]py-
ridin]-5'-yl]-2-thienyl}methanamine
##STR00025##
[0128] The compound of Example 5 may be prepared by a method
analogous to the alternate method of Example 2, or prepared
according to Scheme 2 as detailed below.
##STR00026##
a)
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5-
'-yl]thiophene-2-carbaldehyde
[0129] To a stirred solution of
(2R)-5'-bromo-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin-
e] (Scheme 1, 3.2 g, 10.8 mmol) and (5-formyl-2-thienyl)boronic
acid (3.37 g, 21.6 mmol) in 150 mL DME/H.sub.2O/EtOH (7:3:2),
powdered Na.sub.2CO.sub.3 (4.58 g, 43.2 mmol) was added. The
resulting mixture was purged with N.sub.2 at rt for 15 min, before
the addition of dichloro[bis(triphenylphosphoranyl)]palladium (380
mg, 0.54 mmol). The reaction mixture was purged with N.sub.2 for
another 15 min, before being heated in a 70.degree. C. oil bath
under N.sub.2 for 3-4 h. The reaction mixture was cooled and then
concentrated under reduced pressure. The solid residue was treated
with 150 mL CHCl.sub.3, and the resulting suspension was filtered
through a short pad of diatomaceous earth (the filter cake was
washed with .about.100 mL CHCl.sub.3). The combined filtrate was
concentrated under reduced pressure. The blackish solid was taken
into 0.5 M HCl (100-150 mL) and EtOAc (.about.400 mL). The acidic
aqueous layer was separated and the blackish organic layer was
washed further with 0.5 M HCl (2.times.50 mL). The combined aqueous
layers were then basified with 1 M NaOH to pH .about.12, and
extracted with CHCl.sub.3 (100 mL, then 2.times.50 mL). The
CHCl.sub.3 extracts were dried over MgSO.sub.4, filtered, and
concentrated to give 3.5 g (99%) of
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-y-
l]thiophene-2-carbaldehyde. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 1.50 (dddd, J=12.8, 10.7, 6.7, 2.3 Hz, 1H), 1.68-1.72 (m,
2H), 2.03 (t, J=2.9 Hz, 1H), 2.22-2.26 (m, 1H), 2.78-2.95 (m, 3H),
2.97 (dd, J=14.7, 2.1 Hz, 1H), 3.01-3.05 (m, 1H), 3.08 (d, J=16.5
Hz, 1H), 3.40 (dd, J=14.7, 1.6 Hz, 1H), 3.48 (d, J=16.5 Hz, 1H),
7.29 (d, J=4.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.72 (d, J=4.0 Hz,
1H), 8.36 (d, J=2.2 Hz, 1H), 9.88 (s, 1H); MS ES.sup.+ m/z=327
(M+H.sup.+).
b) To a stirred suspension of
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-y-
l]thiophene-2-carbaldehyde (1.5 g, 4.6 mmol) in 40 mL MeOH, 9.2 mL
methylamine methanolic solution (18.4 mmol) was added. The clear
solution was stirred at rt for 0.5 h before the addition of
NaBH.sub.4 (524 mg, 3.0 equiv) as one portion. The reaction mixture
was stirred at rt for 1 h. The solution was concentrated under
reduced pressure to give a black residue, which was dissolved in 60
mL MeOH and treated with 30 mL 4.0 M HCl. The resulting solution
was heated at 80.degree. C. for 1-2 h. MeOH1 was removed under
reduced pressure. The resulting acidic aqueous solution was
basified by slow addition of cone. aqueous NaOH until pH>12 and
extracted with CHCl.sub.3 (3.times.50 mL). The blackish organic
layers were dried over MgSO.sub.4, filtered and concentrated to
give a black residue, which was then purified by short-packed
silica gel column (5% 7 M NH.sub.3/MeOH in CHCl.sub.3) to give a
yellowish solid, which was washed with minimum amount of Et.sub.2O
(.about.20 mL) to remove minor impurities. Yield: 1.2 g (76%);
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.48 (ddd, J=12.8, 10.7,
6.6, 2.3 Hz, 1H), 1.67-1.70 (m, 2H), 2.02 (t, J=2.9 Hz, 1H),
2.22-127 (m, 1H), 2.50 (s, 3H), 2.77-2.93 (m, 3H), 2.96 (dd,
J=14.7, 2.1 Hz, 1H), 3.01-3.07 (m, 1H), 3.04 (d, J=16.2 Hz, 1H),
3.39 (dd, J=14.7, 1.8 Hz, 1H), 3.43 (d, J=16.2 Hz, 1H), 3.93 (s,
1H), 6.87 (d, J=3.6 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 7.59 (d, J=2.2
Hz, 1H), 8.23 (d, J=2.2 Hz, 1H); MS ES.sup.+ m/z=342
(M+H.sup.+).
Example 6
N-methyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]py-
ridin]-5'-yl]-2-furyl}methenamine
##STR00027##
[0131] This compound was prepared by a process analogous to that
used for Example 5, via Scheme 2. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 1.44-1.50 (m, 1H), 1.67-1.70 (m, 2H), 2.00-2.03 (m, 1H),
2.22-2.27 (m, 1H), 2.48 (s, 3H), 2.79-3.04 (m, 6H), 3.42 (d, J=16.3
Hz, 1H), 3.39 (d, J=15.6 Hz, 1H), 3.78 (s, 2H), 6.24 (d, J=3.1 Hz,
1H), 6.45 (d, J=3.1 Hz, 1H), 7.69 (s, 1H), 8.31 (s, 1H); MS
ES.sup.+, m/z=326 (M+H.sup.+)
Example 7
(2R)-5'-[5-(pyrrolidin-1-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]o-
ctane-2,2'-furo[2,3-b]pyridine]
##STR00028##
[0133] A process analogous to the alternate preparation for Example
2 was used to prepare this compound. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.42-1.52 (dddd, J=2.6, 6.8, 10.2, 12.8 Hz,
1H), 1.66-1.71 (m, 2H), 1.77-1.83 (m, 4H), 1.98-2.03 (m, 1H),
2.21-2.28 (m, 1H), 2.57-2.63 (m, 4H), 2.79-3.05 (m, 6H), 3.39 (d,
J=14.6 Hz, 1H), 3.42 (d, J=16.3 Hz, 1H), 3.68 (s, 2H), 6.25 (d,
J=3.2 Hz, 1H), 6.45 (d, J=3.2 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 8.31
(d, J=2.2 Hz, 1H); MS ES.sup.+, m/z=366 (M+H.sup.+)
Example 8
(2R)-5'-[5-(morpholin-4-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]oc-
tane-2,2'-furo[2,3-b]pridine]
##STR00029##
[0135] A process analogous to the alternate preparation for Example
2 was used to prepare this compound. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 1.42-1.50 (m, 1H), 1.66-1.71 (m, 2H), 2.00-2.04
(m, 1H), 2.20-2.28 (m, 1H), 2.53 (t, J=4.6 Hz, 4H), 2.82-3.06 (m,
6H), 3.39 (d, J=13.8 Hz, 1H), 3.43 (d, J=16.3 Hz, 1H), 3.59 (s,
2H), 3.73 (t, J=4.6 Hz, 4H), 6.28 (d, J=3.4 Hz, 1H), 6.46 (d, J=3.4
Hz, 1H), 7.70 (s, 1H), 8.32 (s, 1H); MS ES.sup.+, m/z=382
(M+H.sup.+).
Example 9
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3--
b]pyridin]-5'-yl]-2-furyl}methenamine
##STR00030##
[0137] A process analogous to the alternate preparation for Example
2 was used to prepare this compound, utilizing
5-formylfuran-3-boronic acid pinacol ester in the Suzuki coupling
in place of the free boronic acid. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 1.57-1.63 (m, 1H), 1.72-1.82 (m, 2H), 2.04 (bs,
1H), 2.15-2.22 (m, 1H), 2.29 (s, 6H), 2.83-2.87 (m, 2H), 2.92-2.97
(m, 2H), 3.06 (d, J=14.6 Hz, 1H), 3.16 (d, J=17 Hz, 1H), 3.26 (d,
J=14.6 Hz, 1H), 3.53 (d, J=18 Hz, 1H), 3.54 (s, 2H), 6.66 (s, 1H),
7.78 (d, J=2 Hz, 1H), 7.82 (s, 1H), 8.07 (d, J=2 Hz, 1H) MS
ES.sup.+, m/z=340 (M+Na.sup.+).
Example 10
(2R)-5'-[5-(pyrrolidin-1-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]o-
ctane-2,2'-furo[2,3-b]pyridine]
##STR00031##
[0139] This compound was prepared by a process analogous to that
used for Example 9,
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-furyl}methenamine. .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 1.57-1.63 (m, 1H), 1.74-1.85 (m, 6H), 2.03 (bs,
1H), 2.17-2.22 (m, 1H), 2.62-2.64 (m, 4H), 2.81-2.87 (m, 2H),
2.92-2.97 (m, 2H), 3.06 (d, J=14.6 Hz, 1H), 3.16 (d, J=17 Hz, 1H),
3.26 (d, J=14.6 Hz, 1H), 3.53 (d, J=16.5 Hz, 1H), 3.69 (s, 2H),
6.64 (s, 1H), 7.77 (d, J=2 Hz, 1H), 7.81 (s, 1H), 8.07 (d, J=2 Hz,
1H) MS ES.sup.+, m/z=366 (M+Na.sup.+).
Example 11
(2R)-5'-[5-(morpholin-4-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]oc-
tane-2,2'-furo[2,3-b]pyridine]
##STR00032##
[0141] This compound was prepared by a process analogous to that
used for Example 9,
N,N-dimethyl-1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-
-b]pyridin]-5'-yl]-2-furyl}methenamine .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 1.57-1.63 (m, 1H), 1.72-1.81 (m, 2H), 2.03 (bs,
1H), 2.18-2.22 (m, 1H), 2.51-2.53 (m, 4H), 2.80-2.86 (m, 2H),
2.92-2.97 (m, 2H), 3.06 (d, J=14.6 Hz, 1H), 3.16 (d, J=17 Hz, 1H),
3.26 (d, J=14.6 Hz, 1H), 3.53 (d, J=16.5 Hz, 1H), 3.59 (s, 2H),
3.68-3.70 (m, 4H), 6.66 (s, 1H), 7.77 (d, J=2 Hz, 1H), 7.82 (s,
1H), 8.07 (d, J=2 Hz, 1H) MS ES.sup.+, m/z=382 (M+Na.sup.+).
Example 12
N-methyl-N-({5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]p-
yridin]-5'-yl]-2-furyl}methyl)cyclopropanamine
##STR00033##
[0143] To a stirred solution of
N-methyl-1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]p-
yridin]-5'-yl]-2-furyl}methenamine (140 mg, 0.4 mmol) as prepared
in Example 6 in 7 mL MeOH,
[(1-ethoxycyclopropyl)oxy](trimethyl)silane (410 mg) was added,
followed by addition of AcOH (340 mg, 5.6 mmol) and NaBH.sub.3CN
(130 mg, 2.0 mmol). The reaction mixture was heated at 65.degree.
C. oil bath overnight. It was then cooled to rt and concentrated
under reduced pressure. The residue was quenched with aqueous
potassium carbonate solution and extracted with CHCl.sub.3
(3.times.30 mL). The organic layers were combined, dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
residue was then purified by silica gel column chromatography (5%
7M NH.sub.3/MeOH in CHCl.sub.3) to give the title compound (90 mg,
62% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 0.41-0.49 (m,
4H), 1.47 (dddd, J=2.4, 6.7, 10.4, 12.8 Hz, 1H), 1.67-1.70 (m, 2H),
1.73 (m, 1H), 1.99-2.01 (m, 1H), 2.21-2.27 (m, 1H), 2.39 (s, 3H),
2.78-2.92 (m, 3H), 2.95 (dd, J=2.4, 14.7 Hz, 1H), 3.03 (d, J=16.5
Hz, 1H), 3.00-3.06 (m, 1H), 3.39 (d, J=14.7 Hz, 1H), 3.42 (d,
J=16.5 Hz, 1H), 3.73 (s, 2H), 6.24 (d, J=3.3 Hz, 1H), 6.46 (d,
J=3.3 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H); MS
ES.sup.+, m/z=366 (M+H.sup.+).
Example 13
N-methyl-N-({4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]p-
yridin]-5'-yl]-2-furyl}methyl)cyclopropanamine
##STR00034##
[0145] This compound was prepared by a process analogous to that
used for Example 12. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta.
0.40-0.42 (m, 2H), 0.49-0.51 (m, 2H), 1.58-1.63 (m, 1H), 1.74-1.82
(m, 3H), 2.04 (bs, 1H), 2.18-2.23 (m, 1H), 2.36 (s, 3H), 2.82-2.86
(m, 2H), 2.94-2.97 (m, 2H), 3.06 (d, J=16 Hz, 1H), 3.16 (d, J=16.5
Hz, 1H), 3.26 (d, J=15 Hz, 1H), 3.53 (d, J=16.5 Hz, 1H), 3.72 (s,
2H), 6.63 (s, 1H), 7.78 (d, J=2 Hz, 1H), 7.81 (s, 1H), 8.08 (d, J=2
Hz, 1H) MS ES.sup.+, m/z=366 (M+Na.sup.+).
[0146] The compounds of Examples 14, 15 and 16 may be prepared by
the process of Scheme 1, or as specifically described.
Example 14
1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-
-yl]-2-furyl}methenamine
##STR00035##
[0148] To a hydrogenation vessel, a spatula tip of Ra--Ni in
aqueous suspension was added. The catalyst was washed with MeOH
(2.times.2 mL), before the addition of 5 mL Methanolic solution of
100 mg (0.32 mmol)
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-y-
l]-2-furaldehyde and 10 mL 7 M NH.sub.3 in MeOH. The hydrogenation
reaction was carried out in a Parr shaker (50 psi, 45.degree. C.,
2-3 h). The catalyst was filtered off, and the filtrate was
concentrated under reduced pressure. The residue was then purified
by silica gel column chromatography (18% MeOH, 2% NH.sub.4OH in
CHCl.sub.3 as eluent) to give the title compound (63 mg, 63%
yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.44-1.51 (dddd,
J=2.4, 6.7, 10.4, 12.8 Hz, 1H), 1.66-1.70 (m, 2H), 2.00-2.03 (m,
1H), 2.21-2.28 (m, 1H), 237-2.93 (m, 3H), 2.95 (dd, J=2.4, 14.7 Hz,
1H), 3.02 (d, J=16.5 Hz, 1H), 3.00-3.07 (m, 1H), 3.39 (d, J=14.7
Hz, 1H), 3.43 (d, J=16.5 Hz, 1H), 3.87 (s, 2H), 6.20 (d, J=3.4 Hz,
1H), 6.44 (d, J=3.4 Hz, 1H), 7.69 (s, 1H), 8.31 (s, 1H)
[0149] MS ES.sup.+, m/z=312 (M+H.sup.+).
Example 15
1-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-
-yl]-2-thienyl}methenamine
##STR00036##
[0151] To a solution of
5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-y-
l]thiophene-2-carbaldehyde (326 mg, 1.0 mmol) in 10 mL MeOH, 0.2 mL
50% hydroxylamine aqueous solution (3.0 mmol) was added. The
reaction mixture was stirred at rt for 2 h, then was concentrated
under reduced pressure to give the oxime intermediate (300 mg,
88%), which was used without any further purification.
[0152] To a stirred solution of oxime (280 mg, 0.8 mmol) in AcOH (4
mL), Zn powder (390 mg, 6 mmol) was added. The reaction mixture was
stirred at rt for 1 h (progress was monitored by LCMS). It was then
diluted with MeOH and filtered. The filtrate was concentrated under
reduced pressure. The residue was quenched with aqueous potassium
carbonate solution and extracted with CHCl.sub.3 (3.times.30 mL).
The organic layers were combined, dried over MgSO.sub.4, filtered
and concentrated under reduced pressure. The residue was then
purified by silica gel column chromatography (18% MeOH, 2%
NH.sub.4OH in CHCl.sub.3 as eluent) to give the title compound
(0.26 g, 99% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 1.47
(dddd, J=2.4, 6.7, 10.4, 12.8 Hz, 1H), 1.68-1.71 (m, 2H), 2.01-2.04
(m, 1H), 2.23-2.27 (m, 1H), 2.78-2.93 (m, 3H), 2.96 (dd, J=2.4,
14.7 Hz, 1H), 3.01-3.07 (m, 1H), 3.04 (d, J=16.3 Hz, 1H), 3.40 (dd,
J=1.2, 14.7 Hz, 1H), 3.44 (d, J=16.3 Hz, 1H), 4.05 (s, 2H), 6.86
(d, J=3.6 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 7.59 (s, 1H), 8.22 (s,
1H); MS ES.sup.+, m/z=328 (M+H.sup.+)
Example 16
1-{4-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-
-yl]-2-furyl}methenamine
##STR00037##
[0154] This compound was prepared by a process analogous to that
used for Example 15. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
1.55-1.65 (m, 1H), 1.69-1.87 (m, 2H), 2.03 (s, 1H), 2.12-2.25 (m,
1H), 2.81-2.97 (m, 2H), 3.06 (d, J=14.7 Hz, 1H), 3.15 (d, J=16.7
Hz, 1H), 3.27 (d, J=14.7 Hz, 1H), 3.51 (d, J=16.7 Hz, 1H), 3.80 (s,
2H), 6.59 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.79 (s, 1H), 8.05 (d,
J=1.8 Hz, 1H); MS ES.sup.+ m/z=312 (M+H.sup.+)
* * * * *