U.S. patent application number 10/162129 was filed with the patent office on 2003-03-06 for pharmaceutical compositions and methods for use.
Invention is credited to Crooks, Peter Anthony, Dull, Gary Maurice, Schmitt, Jeffrey Daniel.
Application Number | 20030045523 10/162129 |
Document ID | / |
Family ID | 22781623 |
Filed Date | 2003-03-06 |
United States Patent
Application |
20030045523 |
Kind Code |
A1 |
Schmitt, Jeffrey Daniel ; et
al. |
March 6, 2003 |
Pharmaceutical compositions and methods for use
Abstract
Pharmaceutical compositions include aryl substituted amine
compounds, and in particular, carbon-linked aromatic azabicyclo
compounds, and in particular, aromatic alkylene azabicyclo
compounds and aromatic alkyl azabicyclo compounds.
Inventors: |
Schmitt, Jeffrey Daniel;
(Winston-Salem, NC) ; Crooks, Peter Anthony;
(Lexington, KY) ; Dull, Gary Maurice; (Lewisville,
NC) |
Correspondence
Address: |
WOMBLE CARLYLE SANDRIDGE & RICE
P.O. BOX 7037
ATLANTA
GA
30357-0037
US
|
Family ID: |
22781623 |
Appl. No.: |
10/162129 |
Filed: |
June 4, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10162129 |
Jun 4, 2002 |
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09210113 |
Dec 11, 1998 |
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6432975 |
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Current U.S.
Class: |
514/242 ;
514/252.04; 514/255.05; 514/256; 514/305; 544/182; 544/238;
544/333; 544/405; 546/135 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 453/02 20130101; A61P 25/18 20180101 |
Class at
Publication: |
514/242 ;
514/252.04; 514/255.05; 514/305; 544/182; 544/405; 544/238;
546/135; 544/333; 514/256 |
International
Class: |
C07D 453/02; C07D
453/04; A61K 031/53; A61K 031/506; A61K 031/501; A61K 031/497 |
Claims
That which is claimed is:
1. A compound having a structure of the formula: 5where the wavy
line in the structure indicates that the bond can be a C--C or
C.dbd.C bond; the dashed line in the structure indicates that the
bond can be a C--C or C.dbd.C bond; and at least one of the wavy or
dashed lines is a C--C bond; X, X.sup.' and X" are individually
nitrogen or carbon bonded to a species hereinafter defined as
A.sup."; A, A.sup.' and A" are individually substituent species
characterized as having a sigma m value which is between about -0.3
and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1
or 2; E, E', E" and E'" individually represent hydrogen, alkyl,
substituted alkyl, halo substituted alkyl, cycloalkyl, substituted
cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or
substituted arylalkyl; either E and E' or E" and E'" and their
associated carbon atom can combine to form a ring structure; either
E and E" or E' and E'" and their associated carbon atoms can
combine to form a ring structure; j is an integer from 0 to 3; and
Z represents a non-hydrogen substitutent.
2. The compound of claim 1 wherein X" is nitrogen or carbon bonded
to A" wherein A" is selected from the group consisting of NR'R"OR'
and NO.sub.2 wherein R' and R" are selected from the group
consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic
heterocyclic ring and an aromatic group-containing species.
3. The compound of claim 2 wherein A" is selected from the group
consisting of NH.sub.2, NHCH.sub.3 or NC(CH.sub.3).sub.2.
4. The compound of claim 1 wherein A and A' are selected from the
groups consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, heterocyclyl, substituted heterocyclyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2, C.sub.2R', SH,
SR', N.sub.3, SO.sub.2R', OR', (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen, alkyl or an aromatic
group-containing species.
5. The compound of claim 1 wherein the dashed line is a C.dbd.C
bond.
6. The compound of claim 1 wherein the wavy line is a C.dbd.C bond
and the compounds have E and Z forms.
7. A compound having a structure of the formula: 6where the wavy
line in the structure indicates that the bond can be a C--C or
C.dbd.C bond; the dashed line in the structure indicates that the
bond can be a C--C or C.dbd.C bond; and at least one of the wavy or
dashed lines is a C--C bond; X, X' and X" are individually nitrogen
or carbon bonded to a species hereinafter defined as A" A, A' and
A" are individually substituent species characterized as having a
sigma m value which is between about -0.3 and about 0.75; n is an
integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E', E" and E'"
individually represent hydrogen, alkyl, substituted alkyl, halo
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl or substituted
arylalkyl; either E and E' or E" and E'" and their associated
carbon atom can combine to form a ring structure; either E and E"
or E' and E'" and their associated carbon atoms can combine to form
a ring structure; j is an integer from 0 to 3; Z represents a
non-hydrogen substitutent, t is 0, 1 or 2; w is an integer from 0
to 3; A.sup.IV is a non-hydrogen substituent selected from the
group consisting of alkyl, alkenyl, substituted alkenyl
heterocyclyl, substituted heterocyclyl, cycloalkenyl, substituted
cycloalkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted
arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2,
C.sub.2R', SH, SR', N.sub.3, SO.sub.2R', OR, (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen, alkyl or an aromatic
containing species.
8. The compound of claim 7 wherein X" is nitrogen or carbon bonded
to A" wherein A" is selected from the group consisting of NR'R",
OR' and NO.sub.2 wherein R' and R" are selected from the group
consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic
heterocyclic ring and an aromatic group-containing species.
9. The compound of claim 8 wherein A" is selected from the group
consisting of NH.sub.2, NHCH.sub.3 or NC(CH.sub.3).sub.2.
10. The compound of claim 7 wherein A and A' are selected from the
groups consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, heterocyclyl, substituted heterocyclyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2, C.sub.2R', SH,
SR', N.sub.3, SO.sub.2R', OR', (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen, alkyl or an aromatic
group-containing species.
11. The compound of claim 7 wherein the dashed line is a C.dbd.C
bond.
12. The compound of claim 7 wherein the wavy line is a C.dbd.C bond
and the compounds have E and Z forms.
13. A pharmaceutical composition incorporating a nicotinic
antagonist, said composition comprising an amount of a compound of
the formula: 7in association with a pharmaceutically acceptable
carrier, wherein said amount is effective to interact with relevant
nicotinic receptor sites of a patient where the wavy line in the
structure indicates that the bond can be a C--C or C.dbd.C bond;
the dashed line in the structure indicates that the bond can be a
C--C or C.dbd.C bond; and at least one of the wavy or dashed lines
is a C--C bond; X, X' and X" are individually nitrogen or carbon
bonded to a species hereinafter defined as A"; A, A' and A" are
individually substituent species characterized as having a sigma m
value which is between about -0.3 and about 0.75; n is an integer
from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E', E" and E'"
individually represent hydrogen, alkyl, substituted alkyl, halo
substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl or substituted
arylalkyl; either E and E' or E" and E'" and their associated
carbon atom can combine to form a ring structure; either E and E"
or E' and E'" and their associated carbon atoms can combine to form
a ring structure; j is an integer from 0 to 3; and Z represents a
non-hydrogen substitutent.
14. The pharmaceutical composition of claim 13 wherein X" is
nitrogen or carbon bonded to A" wherein A" is selected from the
group consisting of NR'R", OR' and NO.sub.2 wherein R' and R" are
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
a non-aromatic heterocyclic ring and an aromatic group-containing
species.
15. The pharmaceutical composition of claim 14 wherein A" is
selected from the group consisting of NH.sub.2, NHCH.sub.3 or
NC(CH.sub.3).sub.2.
16. The pharmaceutical composition of claim 13 wherein A and A' are
selected from the groups consisting of H.sub.1, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted
heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted
arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2,
C.sub.2R', SH, SR', N.sub.3, SO.sub.2R', OR', (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.q C.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen, alkyl or a non-aromatic
heterocyclic ring, or an aromatic group-containing species.
17. The pharmaceutical composition of claim 13 wherein the dashed
line is a C.dbd.C bond.
18. The pharmaceutical composition of claim 13 wherein the wavy
line is a C.dbd.C bond and the compounds have E and Z forms.
19. A pharmaceutical composition incorporating a nicotinic
antagonist, said composition comprising an amount of a compound of
the formula: 8in association with a pharmaceutically acceptable
carrier, wherein said amount is effective to interact with relevant
nicotinic receptor sites of a patient where the wavy line in the
structure indicates that the bond can be a C--C or C.dbd.C bond;
the dashed line in the structure indicates that the bond can be a
C--C or C.dbd.C bond; and at least one of the wavy or dashed lines
is a C--C bond; X, X.sup.I and X.sup.II are individually nitrogen
or carbon bonded to a species hereinafter defined as A.sup.II; A,
A.sup.I and A.sup.II are individually substituent species
characterized as having a sigma m value which is between about -0.3
and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1
or 2; E, E', E" and E'" individually represent hydrogen, alkyl,
substituted alkyl, halo substituted alkyl, cycloalkyl, substituted
cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or
substituted arylalkyl; either E and E' or E" and E'" and their
associated carbon atom can combine to form a ring structure; either
E and E" or E' and E'" and their associated carbon atoms can
combine to form a ring structure; j is an integer from 0 to 3; and
Z represents a non-hydrogen substitutent, t is 0, 1 or 2, w is an
integer from 0 to 3; A.sup.IV is a non-hydrogen substituent
selected from the group consisting of alkyl, alkenyl, substituted
alkenyl heterocyclyl, substituted heterocyclyl, cycloalkenyl,
substituted cycloalkenyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN,
NO.sub.2, C.sub.2R', SH, SR', N.sub.3, SO.sub.2R', OR',
(CR'R").sub.qOR', O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R",
NR'C(.dbd.O)R", C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR',
OC(.dbd.O)R', OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an
integer from 1 to 6 and R' and R" are individually hydrogen, alkyl
or an aromatic group containing species.
20. The pharmaceutical composition of claim 19 wherein X" is
nitrogen or carbon bonded to A" wherein A" is selected from the
group consisting of NR'R"OR' and NO.sub.2 wherein R' and R" are
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
a non-aromatic heterocyclic ring and an aromatic group-containing
species.
21. The pharmaceutical composition of claim 20 wherein A" is
selected from the group consisting of NH.sub.2, NHCH.sub.3 or
NC(CH.sub.3).sub.2.
22. The pharmaceutical composition of claim 19 wherein A and A' are
selected from the groups consisting of H.sub.1, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted
heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted
arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2,
C.sub.2R', SH, SR', N.sub.3, SO.sub.2R', OR, (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen, alkyl, a non-aromatic
heterocyclic ring, or an aromatic group-containing species.
23. The pharmaceutical composition of claim 19 wherein the dashed
line a is C.dbd.C bond.
24. The pharmaceutical composition of claim 19 wherein the wavy
line is a C.dbd.C bond and the compounds have E and Z forms.
25. A method of treating a disorder comprising administering to a
subject having a disorder characterized by an alteration in normal
neurotransmitter release an effective amount of a compound of the
formula: 9where the wavy line in the structure indicates that the
bond can be a C--C or C.dbd.C bond; the dashed line in the
structure indicates that the bond can be a C--C or C.dbd.C bond;
and at least one of the wavy or dashed lines is a C--C bond; X, X'
and X" are individually nitrogen or carbon bonded to a species
hereinafter defined as A"; A, A' and A" are individually
substituent species characterized as having a sigma m value which
is between about -0.3 and about 0.75; n is an integer from 0 to 3;
m is 0, 1 or 2; p is 1 or 2; E, E', E" and E'" individually
represent hydrogen, alkyl, substituted alkyl, halo substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl or substituted arylalkyl; either E
and E' or E" and E'" and their associated carbon atom can combine
to form a ring structure; either E and E" or E' and E'" and their
associated carbon atoms can combine to form a ring structure; j is
an integer from 0 to 3; and Z represents a non-hydrogen
substitutent.
26. The method of treating a disorder of claim 25 whereby X" is
nitrogen or carbon bonded to A" wherein A" is selected from the
group consisting of NR'R", OR' and NO.sub.2 wherein R' and R" are
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
a non-aromatic heterocyclic ring and an aromatic group-containing
species.
27. The method of treating a disorder of claim 26 whereby A" is
selected from the group consisting of NH.sub.2, NHCH.sub.3 or
NC(CH.sub.3).sub.2.
28. The method of treating a disorder of claim 25 whereby A and A'
are selected from the groups consisting of hydrogen, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl,
substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN,
NO.sub.2, C.sub.2R', SH, SR', N.sub.3, SO.sub.2R', OR',
(CR'R").sub.qOR', O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R",
NR'C(.dbd.O)R", C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR',
OC(.dbd.O)R', OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an
integer from 1 to 6 and R' and R" are individually hydrogen, alkyl,
a non-aromatic heterocyclic ring, or an aromatic group-containing
species.
29. The method of claim 25 whereby the dashed line is a C.dbd.C
bond.
30. The method of claim 25 whereby the wavy line is C.dbd.C bond
and the compounds have E and Z forms.
31. A method of treating a disorder comprising administering to a
subject having a disorder characterized by an alteration in normal
neurotransmitter release an effective amount of a compound of the
formula: 10where the wavy line in the structure indicates that the
bond can be a C--C or C.dbd.C bond; the dashed line in the
structure indicates that the bond can be a C--C or C.dbd.C bond;
and at least one of the wavy or dashed lines is a C--C bond; X, X'
and X" are individually nitrogen or carbon bonded to a species
hereinafter defined as A"; A, A' and A" are individually
substituent species characterized as having a sigma m value which
is between about -0.3 and about 0.75; n is an integer from 0 to 3;
m is 0, 1 or 2; p is 1 or 2; E, E', E" and E'" individually
represent hydrogen, alkyl, substituted alkyl, halo substituted
alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,
substituted heterocyclyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl or substituted arylalkyl; either E
and E' or E" and E'" and their associated carbon atom can combine
to form a ring structure; either E and E" or E' and E'" and their
associated carbon atoms can combine to form a ring structure; j is
an integer from 0 to 3; and Z represents a non-hydrogen
substitutent, t is 0.sub.1 1 or 2, w is an integer from 0 to 3;
A.sup.IV is a non-hydrogen substituent selected from the group
consisting of alkyl, alkenyl, substituted alkenyl heterocyclyl,
substituted heterocyclyl, cycloalkenyl, substituted cycloalkenyl,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl,
F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2, C.sub.2R', SH,
SR', N.sub.3, SO.sub.2R', OR', (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen or alkyl.
32. The method of treating a disorder of claim 31 whereby X" is
nitrogen or carbon bonded to A" wherein A" is selected from the
group consisting of NR'R", OR' and NO.sub.2 wherein R' and R" are
selected from the group consisting of hydrogen, alkyl, cycloalkyl,
a non-aromatic heterocyclic ring and an aromatic group-containing
species.
33. The method of treating a disorder of claim 32 whereby A" is
selected from the group consisting of NH.sub.2, NHCH.sub.3 or
NC(CH.sub.3).sub.2.
34. The method of treating a disorder of claim 31 whereby A and A'
are selected from the groups consisting of H.sub.1, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl,
substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl,
substituted arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN,
NO.sub.2, C.sub.2R', SH, SR', N.sub.3, SO.sub.2 R', OR',
(CR'R").sub.qOR', O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R",
NR'C(.dbd.O)R", C(.dbd.O)R", (CR'R").sub.q C.sub.2R', C(.dbd.O)OR',
OC(.dbd.O)R', OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an
integer from 1 to 6 and R' and R" are individually hydrogen, alkyl,
cycloalkyl, a non-aromatic heterocyclic ring, or an aromatic
group-containing species.
35. The method of treating a disorder of claim 31 wherein the
dashed line is a C.dbd.C bond.
36. The method of treating a disorder of claim 31 wherein the wavy
line is a C.dbd.C bond and the compounds have E and Z forms.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to pharmaceutical
compositions, and particularly pharmaceutical compositions
incorporating compounds that are capable of affecting nicotinic
cholinergic receptors. More particularly, the present invention
relates to compounds capable of acting to inhibit function of
certain nicotinic cholinergic receptors, and hence acting as
antagonists at certain specific nicotinic receptor subtypes. The
present invention also relates to methods for treating a wide
variety of conditions and disorders, including conditions and
disorders associated with dysfunction of the central and autonomic
nervous systems.
[0002] Nicotine has been proposed to have a number of
pharmacological effects. See, for example, Pullan et al. N. Engl.
J. Med. 330:811-815 (1994). Certain of those effects may be related
to effects upon neurotransmitter release. See for example,
Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective
effects of nicotine are proposed. Release of acetylcholine and
dopamine by neurons upon administration of nicotine has been
reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et
al., J. Neurochem. 50:1123 (1988); Sandor et al., Brain Res.
567:313 (1991) and Vizi, Br. J. Pharmacol. 47:765 (1973). Release
of norepinephrine by neurons upon administration of nicotine has
been reported by Hall et al., Biochem. Pharmacol. 21:1829 (1972).
Release of serotonin by neurons upon administration of nicotine has
been reported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296:91
(1977). Release of glutamate by neurons upon administration of
nicotine has been reported by Toth et al., Neurochem Res. 17:265
(1992). In addition, nicotine reportedly potentiates the
pharmacological behavior of certain pharmaceutical compositions
used for the treatment of certain disorders. See, Sanberg et al.,
Pharmacol. Biochem. & Behavior 46:303 (1993); Harsing et al.,
J. Neurochem. 59:48 (1993) and Hughes, Proceedings from Intl. Symp.
Nic. S40 (1994). Furthermore, various other beneficial
pharmacological effects of nicotine have been proposed. See, Decina
et al., Biol. Psychiatry 28:502 (1990); Wagner et al.,
Pharmacopsychiatry 21:301 (1988); Pomerleau et al., Addictive
Behaviors 9:265 (1984); Onaivi et al., Life Sci. 54(3):193 (1994);
Tripathi et al., JPET 221: 91-96 (1982); and Hamon, Trends in
Pharmacol. Res. 15:36.
[0003] Various nicotinic compounds have been reported as being
useful for treating a wide variety of conditions and disorders.
See, for example, Williams et al. DN&P 7(4):205-227 (1994),
Arneric et al., CNS Drug Rev. 1(1):1-26 (1995), Arneric et al.,
Exp. Opin. Invest. Drugs 5(1):79-100 (1996), Bencherifet al., JPET
279:1413 (1996), Cosford et al., J. Med. Chem. 39: 3235-3237
(1996), Lippiello et al., JPET 279:1422 (1996), Damaj et al.,
Neuroscience (1997), Holladay et al., J. Med. Chem. 40(28):
4169-4194 (1997), Bannon et al., Science 279: 77-80 (1998), PCT WO
94/08992, PCT WO 96/31475, and U.S. Pat. Nos. 5,583,140 to
Bencherif et al., 5,597,919 to Dull et al., and 5,604,231 to Smith
et al. Nicotinic compounds are reported as being particularly
useful for treating a wide variety of Central Nervous System (CNS)
disorders.
[0004] CNS disorders are a type of neurological disorder. CNS
disorders can be drug induced; can be attributed to genetic
predisposition, infection or trauma; or can be of unknown etiology.
CNS disorders comprise neuropsychiatric disorders, neurological
diseases and mental illnesses; and include neurodegenerative
diseases, behavioral disorders, cognitive disorders and cognitive
affective disorders. There are several CNS disorders whose clinical
manifestations have been attributed to CNS dysfunction (i.e.,
disorders resulting from inappropriate levels of neurotransmitter
release, inappropriate properties of neurotransmitter receptors,
and/or inappropriate interaction between neurotransmitters and
neurotransmitter receptors). Several CNS disorders can be
attributed to a cholinergic abnormality, a dopaminergic
abnormality, an adrenergic abnormality and/or a serotonergic
abnormality. CNS disorders of relatively common occurrence include
presenile dementia (early onset Alzheimer's disease), senile
dementia (dementia of the Alzheimer's type), Parkinsonism including
Parkinson's disease, Huntington's chorea, tardive dyskinesia,
hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia,
schizophrenia, Tourette's syndrome and neuroendocrine disorders
(e.g., obesity, bulemia and diabetes insipidus).
[0005] Nicotinic receptor antagonists have been used for the
treatment of certain disorders. For example, mecamylamine has been
marketed as Inversine by Merck & Co. Inc. as an
antihypertensive agent; and trimethaphan has been marketed as
Arfonad by Roche Laboratories as a vasodepressor agent. See,
Goodman and Gilman's The Pharmacological Basis of Therapeutics,
6.sup.th Ed. p. 217 (1980). Nicotinic receptors have been
implicated in convulsions, such as those that occur as a result of
autosomal dominant nocturnal frontal lobe epilepsy. See, Steinlein
et al., Nat. Genet. 11: 201-203 (1996). Nicotinic antagonists have
been reported to inhibit viral infection. For example, nicotinic
antagonists have been reported to inhibit the infection of dorsal
root ganglion neurons by the rabies virus. See, Castellanos et al.,
Neurosci. Lett. 229: 198-200 (1997). Other uses for nicotinic
antagonists have been proposed. See, for example, Popik et al.,
JPET 275: 753-760 (1995) and Rose et al., Clin. Pharm. Ther. 56(1):
86-9 (1994).
[0006] Nicotinic receptor ligands that interact with the alpha 7
receptor subtype have been proposed to be useful in the treatment
of schizophrenia. There are a decreased number of hippocampal
nicotinic receptors in postmortem brain tissue of schizophrenic
patients. Also, there is improved psychological affect in smoking
versus non-smoking schizophrenic patients. Nicotine improves
sensory gating deficits in animals and schizophrenics. Blockade of
the alpha 7 nicotinic receptor subtype induces a gating deficit
similar to that seen in schizophrenia. See, Leonard et al.,
Schizophrenia Bulletin 22(3): 431-45 (1996). Biochemical,
molecular, and genetic studies of sensory processing in patients
with the P50 auditory-evoked potential gating deficit suggest that
the alpha 7 nicotinic receptor subtype may function in an
inhibitory neuronal pathway. See, Freedman et al., Biological
Psychiatry 38(1):22-33 (1995).
[0007] It would be desirable to provide a useful method for the
prevention and treatment of a condition or disorder by
administering a nicotinic compound to a patient susceptible to or
suffering from such a disorder. It would be highly beneficial to
provide individuals suffering from certain disorders with
interruption of the symptoms of those disorders by the
administration of a pharmaceutical composition containing an active
ingredient having nicotinic pharmacology and providing a beneficial
effect, but which does not provide any significant associated side
effects (e.g., increased heart rate and blood pressure attendant
with interaction of that compound with cardiovascular sites). It
would be highly desirable to provide a pharmaceutical composition
incorporating a compound that interacts with nicotinic receptors,
but which composition does not significantly effect those receptor
subtypes which have the potential to induce undesirable side
effects (e.g., appreciable cardiovascular effects and appreciable
activity at skeletal muscle sites).
SUMMARY OF THE INVENTION
[0008] The present invention relates to carbon-linked aromatic
azabicyclo compounds, and in particular, aromatic alkylene
azabicyclo compounds, aromatic alkyl azabicyclo compounds and
oxacyclic alkyl azabicyclo compounds. Representative compounds are
2-((3-pyridyl)methyl)-1-azabicycl- o[2.2.2]octane,
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one,
2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane and
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol,
2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-one.
[0009] The present invention also relates to methods for
synthesizing those types of compounds. The present invention also
relates to prodrug derivatives of the compounds of the present
invention.
[0010] Compounds of the present invention exhibit activity at
acetylcholine receptors and are useful towards modulating release
of ligands involved in neurotransmission. Compounds of the present
invention are selective to certain nicotinic acetylcholine receptor
subtypes, and can act as antagonists at those receptor subtypes.
Hence, the present invention relates to methods for modulating the
activity of certain nicotinic acetylcholine receptor subtypes by
administering a compound of the present invention.
[0011] The present invention also relates to methods for the
prevention or treatment of conditions and disorders. The present
invention also relates to methods for the prevention or treatment
of conditions and disorders, including central nervous system (CNS)
disorders, which are characterized by an alteration in normal
neurotransmitter release. The methods involve administering to a
subject an effective amount of a compound of the present
invention.
[0012] The present invention, in another aspect, relates to a
pharmaceutical composition comprising an effective amount of a
compound of the present invention. Such a pharmaceutical
composition incorporates a compound that, when employed in
effective amounts, has the capability of interacting with relevant
nicotinic receptor sites of a subject, and hence has the capability
of acting as a therapeutic agent in the prevention or treatment of
disorders characterized by an alteration in normal neurotransmitter
release. Preferred pharmaceutical compositions comprise novel
compounds of the present invention.
[0013] The compounds of the present invention are beneficial in
therapeutic applications requiring a selective inhibition at
certain nicotinic receptor subtypes; that is, the compounds are
antagonists at certain nicotinic receptor subtypes. The
pharmaceutical compositions of the present invention are useful for
the prevention and treatment of a wide variety of conditions or
disorders. The compounds of the present invention are useful for
treating certain CNS conditions and disorders; such as in providing
neuroprotection, in treating patients susceptible to convulsions,
in treating depression, in treating autism, in treating certain
neuroendocrine disorders, and in the management of stroke. The
compounds of the present invention also are useful in treating
hypertension, for effecting weight loss, in treating type II
diabetes and neoplasia, or as anti-bacterial or antiviral agents.
The compounds of the present invention also are useful, when
appropriately radio-labeled, as probes in life science applications
(e.g., as selective probes in neuroimaging applications).
[0014] The pharmaceutical compositions provide therapeutic benefit
to individuals suffering from such conditions or disorders and
exhibiting clinical manifestations of such conditions or disorders,
in that the compounds within those compositions, when employed in
effective amounts, have the potential to (i) exhibit nicotinic
pharmacology and affect relevant nicotinic receptors sites (e.g.,
act as a pharmacological antagonists at nicotinic receptors), and
(ii) modulate neurotransmitter secretion, and hence prevent and
suppress the symptoms associated with those diseases. In addition,
the compounds are expected to have the potential to (i) increase
the number of nicotinic cholinergic receptors of the brain of the
patient, (ii) exhibit neuroprotective effects and (iii) when
employed in effective amounts, not cause appreciable adverse side
effects (e.g., significant increases in blood pressure and heart
rate, significant negative effects upon the gastro-intestinal
tract, and significant effects upon skeletal muscle). The
pharmaceutical compositions of the present invention are believed
to be safe and effective with regards to prevention and treatment
of various conditions or disorders.
[0015] The foregoing and other aspects of the present invention are
explained in detail in the detailed description and examples set
forth below.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The compounds of the present invention include compounds of
the formula: 1
[0017] where the wavy line in the structure indicates that the bond
can be a C--C or C.dbd.C bond; the dashed line in the structure
indicates that the bond can be a C--C or C.dbd.C bond; and at least
one of the wavy or dashed lines is a C--C bond; X, X.sup.I and
X.sup.II are individually nitrogen or carbon bonded to a species
hereinafter defined as A.sup.II. A, A.sup.I and A.sup.II are
individually substituent species characterized as having a sigma m
value greater than 0, often greater than 0.1, and generally greater
than 0.2, and even greater than 0.3; less than 0 and generally less
than -0.1; or 0; as determined in accordance with Hansch et al.,
Chem. Rev. 91:165 (1991) (but preferably, each substituent species
has a sigma m value which is between about -0.3 and about 0.75, and
frequently is between about -0.25 and about 0.6, and each
individual substituent species can have a sigma m value of 0); n is
an integer from 0 to 3, preferably 0, 1 or 2, and more preferably 0
or 1, and most preferably 0; m is 0, 1 or 2, preferably 1; p is 1
or 2 preferably 2; E, E.sup.I, E.sup.II and E.sup.III individually
represent hydrogen, alkyl (e.g., straight chain or branched alkyl
including C.sub.1-C.sub.8, preferably C.sub.1-C.sub.5, such as
methyl, ethyl, or isopropyl), substituted alkyl, halo substituted
alkyl (e.g., straight chain or branched alkyl including
C.sub.1-C.sub.8, preferably C.sub.1-C.sub.5, such as
trifluoromethyl or trichloromethyl), cycloalkyl, substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclyl,
substituted heterocyclyl, aryl, substituted aryl, alkylaryl,
substituted alkylaryl, arylalkyl or substituted arylalkyl; all of
E, E.sup.I, E.sup.II, E.sup.III can be hydrogen, or at least one of
E, E.sup.I, E.sup.II, E.sup.III is non-hydrogen (e.g., alkyl,
substituted alkyl, halo substituted alkyl, cycloalkyl, substituted
cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl,
substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or
substituted arylalkyl) and the remaining E, E.sup.I, E.sup.II,
E.sup.III are hydrogen; either E and E.sup.I or E.sup.II and
E.sup.III and their associated carbon atom can combine to form a
ring structure such as cyclopentyl, cyclohexyl or cycloheptyl;
either E and E.sup.II or E.sup.I and E.sup.III and their associated
carbon atoms can combine to form a ring structure such as
cyclopentyl, cyclohexyl or cycloheptyl; j is an integer from 0 to
3, preferably 0 or 1; Z represents a non-hydrogen substitutent,
such as alkyl (e.g., straight chain or branched alkyl including
C.sub.1-C.sub.8, preferably C.sub.1-C.sub.5, such as methyl, ethyl,
or isopropyl), substituted alkyl, acyl, hydroxy, alkoxy,
alkoxycarbonyl or aryloxycarbonyl, or oxygen (e.g., thereby forming
a carbonyl functionality). More specifically, A and A.sup.I include
H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,
heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted
cycloalkyl, aryl, substituted aryl, alkylaryl, substituted
alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR'R",
CF.sub.3, OH, CN, NO.sub.2, C.sub.2R', SH, SR', N.sub.3,
SO.sub.2R', OR', (CR'R").sub.qOR', O--(CR'R").sub.qC.sub.2R', SR',
C(.dbd.O)NR'R", NR'C(.dbd.O)R", C(.dbd.O)R', (CR'R").sub.q
C.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R', OC(.dbd.O)NR'R" and
NR'C(.dbd.O)OR" where q is an integer from 1 to 6 and R' and R" are
individually hydrogen or alkyl (e.g., C.sub.1-C.sub.10 alkyl,
preferably C.sub.1-C.sub.5 alkyl, and more preferably methyl,
ethyl, isopropyl or isobutyl), cycloalkyl (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl), a
non-aromatic heterocyclic ring wherein the heteroatom of the
heterocyclic moiety is separated from any other nitrogen, oxygen or
sulfur atom by at least two carbon atoms (e.g., quinuclidinyl,
pyrrolidinyl, and piperidinyl), an aromatic group-containing
species (e.g., pyridyl, quinolinyl, pyrimidinyl, furanyl, phenyl,
and benzyl where any of the foregoing can be suitably substituted
with at least one substituent group, such as alkyl, alkoxyl, halo,
or amino substituents). Other representative aromatic ring systems
are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996).
Typically, X.sup.II is nitrogen or carbon bonded to A.sup.II, where
A.sup.II most preferably includes NR'R", OR' and NO.sub.2, where R'
and R" are as defined hereinbefore. Typically, A.sup.II is
NH.sub.2, NHCH.sub.3 or N(CH.sub.3).sub.2, with NH.sub.2 being most
preferred. Preferably, when X.sup.II is carbon bonded to A.sup.II,
A.sup.I is not a substituent bonded to the carbon of the ring (as
shown in the structure) through an oxygen atom. Typically, X is
carbon bonded to A.sup.II, preferably hydrogen. Typically, X.sup.I
is nitrogen or carbon bonded to A.sup.II. Either A.sup.I and a
substituent of X.sup.I or A.sup.O and a substituent of X.sup.II can
combine to form one or more saturated or unsaturated, substituted
or unsubstituted carbocyclic or heterocyclic rings containing, but
not limited to, ether, acetal, thioether, thioester, ketal, amine,
ketone, lactone, lactam, carbamate, or urea functionalities. In
addition, it is highly preferred that A is hydrogen and it is
preferred that A.sup.I is hydrogen. Preferably, E, E.sup.I and
E.sup.II are hydrogen. In one preferred embodiment, n is 1 or 2, E,
E.sup.I and E.sup.II each are hydrogen, and E.sup.III is alkyl
(e.g., methyl) or akylaryl. In another preferred embodiment, n is 1
or 2 and E, E.sup.I, E.sup.II, E.sup.III each are hydrogen.
Depending upon the identity and positioning of each individual E,
E.sup.I, E.sup.II and E.sup.III, certain compounds can be optically
active, and/or can exist in the E or Z form. Additionally,
compounds of the present invention can have chiral centers within
the side chain (e.g., the compound can have an R or S
configuration). Depending upon E, E.sup.I, E.sup.II and E.sup.III,
compounds of the present invention have chiral centers, and the
present invention relates to racemic mixtures of such compounds as
well as single enantiomers. Typically, the selection of n, E,
E.sup.I, E.sup.II and E.sup.III is such that up to about 4, and
frequently up to 3, and usually 0, 1 or 2, of the substituents
designated as E, E.sup.I, E.sup.II and E.sup.III are non-hydrogen
substituents (i.e., substituents such as alkyl or halo-substituted
alkyl). Typically, when X.sup.II is N, it is preferred that A.sup.I
is H, Br or OR' (where R' preferably is methyl, ethyl, isopropyl,
isobutyl or tertiary butyl).
[0018] As employed herein, "alkyl" refers to straight chain or
branched alkyl radicals including C.sub.1-C.sub.8, preferably
C.sub.1-C.sub.5, such as methyl, ethyl, or isopropyl; "substituted
alkyl" refers to alkyl radicals further bearing one or more
substituent groups such as hydroxy, alkoxy, mercapto, aryl,
heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like;
"alkenyl" refers to straight chain or branched hydrocarbon radicals
including C.sub.1-C.sub.8, preferably C.sub.1-C.sub.5 and having at
least one carbon-carbon double bond; "substituted alkenyl" refers
to alkenyl radicals further bearing one or more substituent groups
as defined above; "cycloalkyl" and "cycloalkenyl" refer to
saturated or unsaturated cyclic ring-containing radicals containing
three to eight carbon atoms, preferably three to six carbon atoms;
"substituted cycloalkyl" refers to cycloalkyl radicals further
bearing one or more substituent groups as defined above; "aryl"
refers to aromatic radicals having six to ten carbon atoms;
"substituted aryl" refers to aryl radicals further bearing one or
more substituent groups as defined above; "alkylaryl" refers to
alkyl-substituted aryl radicals; "substituted alkylaryl" refers to
alkylaryl radicals further bearing one or more substituent groups
as defined above; "arylalkyl" refers to aryl-substituted alkyl
radicals; "substituted arylalkyl" refers to arylalkyl radicals
further bearing one or more substituent groups as defined above;
"heterocyclyl" refers to saturated or unsaturated cyclic radicals
containing one or more heteroatoms (e.g., O, N, S) as part of the
ring structure and having two to seven carbon atoms in the ring;
"substituted heterocyclyl" refers to heterocyclyl radicals further
bearing one or more substituent groups as defined above; "acyl"
refers to straight chain or branched alkyl-, alkenyl-, or
substituted alkyl-carbonyl radicals including C.sub.1-C.sub.8,
preferably C.sub.1-C.sub.5, such as formyl, acetyl, or propanoyl;
"alkoxycarbonyl" refers to an alkyl or substituted alkyl radical
attached to an O-carbonyl moiety; and "aryloxycarbonyl" refers to
an aryl or substituted aryl radical attached to an O-carbonyl
moiety.
[0019] Certain preferred compounds of the present invention can be
represented by the formula: 2
[0020] where X, X.sup.I, X.sup.II, A, A.sup.I, E, E.sup.I,
E.sup.II, E.sup.III, n, p, m, j and Z are as defined
hereinbefore.
[0021] Certain other preferred compound of the present invention
can be represented by the formula: 3
[0022] where X, X.sup.I, X.sup.II, A, A.sup.I, E, E.sup.I,
E.sup.II, n, p, m, j and Z are as defined hereinbefore. Such
compounds can have both E and Z forms, can be synthesized as
isomeric mixtures, and can be separated into pure enantiomers by
techniques such as chromographic techniques.
[0023] Certain other preferred compounds of the present invention
can be represented by the formula: 4
[0024] where A, A.sup.I, A.sup.II, A.sup.III, E, E.sup.I, E.sup.II,
E.sup.III, n, p, m, j and Z are as defined hereinbefore; and t is
0, 1 or 2, usually 0 or 1; w is an integer from 0 to 3, preferably
0 or 1; A.sup.IV represents a non-hydrogen substitutent, including
alkyl, substituted alkyl, alkenyl, substituted alkenyl,
heterocyclyl, substituted heterocyclyl, cycloalkenyl, substituted
cycloalkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted
arylalkyl, F, Cl, Br, I, NR'R", CF.sub.3, OH, CN, NO.sub.2,
C.sub.2R', SH, SR', N.sub.3, SO.sub.2R', OR', (CR'R").sub.qOR',
O--(CR'R").sub.qC.sub.2R', SR', C(.dbd.O)NR'R", NR'C(.dbd.O)R",
C(.dbd.O)R', (CR'R").sub.qC.sub.2R', C(.dbd.O)OR', OC(.dbd.O)R',
OC(.dbd.O)NR'R" and NR'C(.dbd.O)OR" where q is an integer from 1 to
6 and R' and R" are individually hydrogen or alkyl (e.g.,
C.sub.1-C.sub.10 alkyl, preferably C.sub.1-C.sub.5 alkyl, and more
preferably methyl, ethyl, isopropyl or isobutyl), cycloalkyl or
cycloalkenyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and adamantyl).
[0025] Representative compounds of the present invention are as
follows:
[0026] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0027] 2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0028] 2-((5-amino-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0029]
2-((5-methoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0030] 2-((5-ethoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0031]
2-((5-isopropoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0032]
2-((5-tert-butoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0033]
2-((5-benzyloxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0034]
2-((5-hydroxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0035]
2-((5-ethynyl-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0036] 2-((5-cyano-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0037] 2-((6-methyl-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0038] 2-((6-fluoro-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0039] 2-((6-chloro-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0040] 2-((6-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0041] 2-((6-iodo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane
[0042] 2-((3-aminophenyl)methyl)-1-azabicyclo[2.2.2]octane
[0043] 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
[0044]
2-((5-methoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
[0045]
2-((5-ethoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
[0046]
2-((5-isopropoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
[0047]
2-((5-tert-butoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
[0048]
2-((5-benzyloxy-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
[0049] 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]
octane
[0050]
2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octane
[0051]
2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane
[0052] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-2-ene
[0053]
2-((5-methoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-2-ene
[0054] 2-((5-ethoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]
oct-2-ene
[0055] 2-((5-isopropoxy-3-pyridyl)methyl)-1-azabicyclo
[2.2.2]oct-2-ene
[0056] 2-((5-tert-butoxy-3-pyridyl)methyl)-1-azabicyclo
[2.2.2]oct-2-ene
[0057]
2-((5-benzyloxy-3-pyridyl)methyl)-1-azabicyclo[2.2.2]oct-2-ene
[0058]
3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane
[0059]
3-(phenylmethoxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane
[0060]
3-((2-phenyl)ethoxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane
[0061] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptane
[0062]
2-((5-methoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptane
[0063]
2-((5-ethoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptane
[0064] 2-((5-isopropoxy-3-pyridyl)methyl)-1-azabicyclo
[2.2.1]heptane
[0065]
2-((5-tert-butoxy-3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptane
[0066]
2-((5-benzyloxy-3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptane
[0067] 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptane
[0068]
2-((5-methoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptane
[0069]
2-((5-ethoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptane
[0070] 2-((5-isopropoxy-3-pyridyl)methylene)-1-azabicyclo
[2.2.1]heptane
[0071]
2-((5-tert-butoxy-3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptane
[0072]
2-((5-benzyloxy-3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptane
[0073] 2-((3-pyridyl)methyl)-1-azabicyclo[3.2.1]octane
[0074]
2-((5-methoxy-3-pyridyl)methyl)-1-azabicyclo[3.2.1]octane
[0075] 2-((5-ethoxy-3-pyridyl)methyl)-1-azabicyclo[3.2.1]octane
[0076]
2-((5-isopropoxy-3-pyridyl)methyl)-1-azabicyclo[3.2.1]octane
[0077]
2-((5-tert-butoxy-3-pyridyl)methyl)-1-azabicyclo[3.2.1]octane
[0078]
2-((5-benzyloxy-3-pyridyl)methyl)-1-azabicyclo[3.2.1]octane
[0079] 2-((3-pyridyl)methylene)-1-azabicyclo[3.2.1]octane
[0080]
2-((5-methoxy-3-pyridyl)methylene)-1-azabicyclo[3.2.1]octane
[0081]
2-((5-ethoxy-3-pyridyl)methylene)-1-azabicyclo[3.2.1]octane
[0082]
2-((5-isopropoxy-3-pyridyl)methylene)-1-azabicyclo[3.2.1]octane
[0083]
2-((5-tert-butoxy-3-pyridyl)methylene)-1-azabicyclo[3.2.1]octane
[0084]
2-((5-benzyloxy-3-pyridyl)methylene)-1-azabicyclo[3.2.1]octane
[0085] Other representative compounds of the present invention
include:
[0086] 2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octane
[0087] 2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-one
[0088] 2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-ol
[0089] 2-(2-(3-pyridyl)ethylene)-1-azabicyclo[2.2.2]octane
[0090] 2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]oct-2-ene
[0091] 2-(3-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane
[0092] 2-(3-(3-pyridyl)propylene)-1-azabicyclo[2.2.2]octane
[0093] 2-(3-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]oct-2-ene
[0094] 2-(4-(3-pyridyl)butyl)-1-azabicyclo[2.2.2]octane
[0095] 2-(4-(3-pyridyl)butylene)-1-azabicyclo[2.2.2]octane
[0096] 2-(4-(3-pyridyl)butyl)-1-azabicyclo[2.2.2]oct-2-ene
[0097] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol
[0098] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one
[0099] 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol
[0100] 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one
[0101] 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo
[2.2.2]octan-3-ol
[0102]
2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-ol
[0103]
2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octan-3-ol
[0104]
2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one
[0105]
2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-one
[0106]
2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octan-3-one
[0107] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptan-3-ol
[0108] 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.1]heptan-3-one
[0109] 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptan-3-ol
[0110] 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.1]heptan-3-one
[0111] 2-((3-pyridyl)methyl)-1-azabicyclo[3.2.1]octan-3-ol
[0112] 2-((3-pyridyl)methyl)-1-azabicyclo[3.2.1]octan-3-one
[0113] 2-((3-pyridyl)methylene)-1-azabicyclo[3.2.1]octan-3-ol
[0114] 2-((3-pyridyl)methylene)-1-azabicyclo[3.2.1]octan-3-one
[0115] 2-((3-furyl)methylene)-1-azabicyclo[2.2.2]octane
[0116] 2-((3-furyl)methyl)-1-azabicyclo [2.2.2]octane
[0117] 2-((3-oxolanyl)methylene)-1-azabicyclo[2.2.2]octane
[0118]
2-((4-methoxy-3-oxolanyl)methylene)-1-azabicyclo[2.2.2]octane
[0119]
2-((4-ethoxy-3-oxolanyl)methylene)-1-azabicyclo[2.2.2]octane
[0120]
2-((4-isopropoxy-3-oxolanyl)methylene)-1-azabicyclo[2.2.2]octane
[0121]
2-((4-benzyloxy-3-oxolanyl)methylene)-1-azabicyclo[2.2.2]octane
[0122] 2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octane
[0123]
2-((4-methoxy-3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octane
[0124]
2-((4-ethoxy-3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octane
[0125]
2-((4-isopropoxy-3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octane
[0126]
2-((4-benzyloxy-3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octane
[0127] The manner in which 2-(3-(4-, 5-, and
6-substituted)pyridylmethyl)-- 1-azabicyclo[2.2.2]octanes of the
present invention can be synthesized can vary. For example,
5-bromopyridine-3-carboxaldehyde and quinuclidin-3-one
hydrochloride (commercially available from Aldrich), are reacted
together in the presence of methanolic potassium hydroxide as
described in Neilsen and Houlihan, Org. React. 16: 1-438 (1968).
This aldol condensation product,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one, is
then treated with sodium borohydride to yield the alcohol,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-ol as a
crystalline solid. This intermediate is reacted with neat thionyl
chloride at room temperature to give
3-chloro-2-(3-(5-bromo)pyridylmethyl-
ene)-1-azabicyclo[2.2.2]octane as a pure crystalline solid.
Reductive removal of the chlorine is accomplished by lithium
trimethoxyaluminum hydride and copper iodide as described by
Masamune et al., J. Am. Chem. Soc. 95: 6452 (1973) to give the
desired product, 2-(3-(5-bromo)pyridylme-
thylene)-1-azabicyclo[2.2.2]octane, as a crystalline solid. This
methylene intermediate can the be converted to the desired product,
2-(3-(5-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]octane, by
hydrogenation in the presence of palladium catalyst. Reaction
conditions are controlled to avoid removal of the bromine
substituent. The isomeric compounds,
2-(3-(4-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]octane and
2-(3-(6-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]octane can be
prepared in a similar manner by replacing
5-bromopyridine-3-carboxaldehyde with
4-bromopyridine-3-carboxaldehyde or
6-bromopyridine-3-carboxaldehyde, respectively, in the synthetic
approach given above.
[0128] The required aldehyde, 5-bromopyridine-3-carboxaldehyde, can
be prepared from 5-bromonicotinic acid (commercially available from
Aldrich Chemical Company and Lancaster Synthesis, Inc.). The
5-bromonicotinic acid can be treated with ethyl chloroformate
producing the mixed anhydride, which can be reduced with lithium
aluminum hydride in tetrahydrofuran (THF) at -78.degree. C., to
afford 5-bromo-3-hydroxymethylpyridine, as reported by A. Ashimori
et al., Chem. Pharm. Bull. 38(9): 2446-2458 (1990). Alternatively,
the 5-bromonicotinic acid can be esterified in the presence of
sulfuric acid and ethanol, and the intermediate ethyl ester can be
reduced with an excess of sodium borohydride to yield
5-bromo-3-hydroxymethylpyridine, according to the techniques
reported in C. F. Nutaitis et al., Org. Prep. and Proc. Int.
24:143-146 (1992). The resulting 5-bromo-3-hydroxymethylpyridine
can then be converted to 5-bromo-3-pyridinecarboxaldehyde by Swern
oxidation using oxalyl chloride and dimethylsulfoxide according to
the methods of M. J. Stocks et al., Tetrahedron Lett. 36(36):
6555-6558 (1995) and A. J. Mancuso et al., J. Org. Chem. 44(23):
4148-4150 (1979). The aldehyde, 4-bromopyridine-3-carboxaldehyde
can be synthesized according to methodology described by Chin et
al. PCT WO 94/29893 or by methodology described by Ojea et al.,
Synlett. 6: 622-624 (1995). 6-Bromopyridine-3-carboxaldehyde can be
prepared according to procedures described in Windschief and
Voegtle, Synthesis 1: 87-92 (1994) or Fey et al German Patent No.
93/4320432.
[0129] The manner in which E and Z isomers of 2-(3-(4-, 5-, and
6-substituted)pyridylmethylene)-1-azabicyclo[2.2.2]octanes of the
present invention can be synthesized can vary. For example,
5-bromopyridine-3-carboxaldehyde and quinuclidin-3-one
hydrochloride (commercially available from Aldrich) are reacted
together in the presence of methanolic potassium hydroxide as
described in Neilsen and Houlihan, Org. React. 16: 1-438 (1968).
This aldol condensation product,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one, is
then treated with sodium borohydride to yield the alcohol,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-ol as a
crystalline solid. This intermediate is reacted with neat thionyl
chloride at room temperature to give
3-chloro-2-(3-(5-bromo)pyridylmethyl-
ene)-1-azabicyclo[2.2.2]octane as a crystalline solid. Reductive
removal of the chlorine is accomplished by lithium
trimethoxyaluminum hydride and copper iodide as described by
Masamune et al., J. Am. Chem. Soc. 95: 6452 (1973) to give the
desired product, 2-(345-bromo)pyridylmethylene)-1-azab-
icyclo[2.2.2]octane. The isomeric compounds,
243-(4-bromo)pyridylmethylene- )-1-azabicyclo[2.2.2]octane and
2-(3-(6-bromo)pyridylmethylene)-1-azabicyc- lo[2.2.2]octane can be
prepared in a similar manner by replacing
5-bromopyridine-3-carboxaldehyde with
4-bromopyridine-3-carboxaldehyde or
6-bromopyridine-3-carboxaldehyde, respectively, in the synthetic
approach given above.
[0130] The manner in which
2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]oc- tane is
synthesized can vary. For example, in one method,
3-nitrobenzaldehyde can be condensed with 3-quinuclidinone in an
aldol reaction using potassium hydroxide and ethanol to yield
2-[(3-nitrophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The
latter compound can be converted to the corresponding dithioketal
by treatment with 1,2-ethanedithiol and boron triflouride etherate.
Reduction and desulfurization can be effected by hydrogenation
using Raney nickel to yield
2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane. Alternatively,
in another method, the aldol product,
2-[(3-nitrophenyl)methylene]-1-azab- icyclo[2.2.2]octan-3-one can
be reduced by treatment with sodium borohydride in methanol to give
the alcohol, 2-[(3-nitrophenyl)methylene]-
-1-azabicyclo[2.2.2]octan-3-ol. The latter compound can be
converted to the chloro intermediate,
3-chloro-2-[(3-nitrophenyl)methylene]-1-azabicyc- lo[2.2.2]octane
dihydrochloride upon treatment with thionyl chloride.
Dechlorination by hydrogenation with Raney nickel and carbon-carbon
double bond reduction by hydrogenation over 10% palladium on carbon
can then be effected to yield
2-[(3-aminophenyl)methyl]-1-azabicyclo[2.2.2]oc- tane. Replacement
of 3-nitrobenzaldehyde with 2-nitrobenzaldehyde or
4-nitrobenzaldehyde in the above synthetic approach affords the
isomeric compounds,
2-[(2-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane and
2-[(4-aminophenyl)methyl]-1-azabicyclo[2.2.2]octane,
respectively.
[0131] The manner in which 2-[(2-, 3-, and 4substituted
phenyl)methyl]-1-azabicyclo[2.2.2]octanes are synthesized can vary.
For example, in one method, 3-bromobenzaldehyde can be subjected to
an aldol reaction with 3-quinuclidinone hydrochloride (commercially
available from Aldrich Chemical Company) using potassium hydroxide
in methanol to give
2-[(3-bromophenyl)methylene]-1-azabicyclo[2.2.2]octan-3-one. The
latter unsaturated ketone can be reduced by hydrogenation using
palladium over charcaol to give
2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octan-3-one- .
Depending upon the choice of hydrogenation catalyst, it may be
necessary to use suitable inhibitors to suppress dihologenation.
For suitable catalysts and inhibitors, see Rylander, Catalytic
Hydrogenation in Organic Synthesis, pp. 125-126 (1979). The
resulting ketone can be reduced under Wolff-Kishner conditions with
hydrazine and base (or under modified Wolff-Kishner conditions with
tosylhydrazine and sodium cyanoborohydride) to yield
2-[(3-bromophenyl) methyl]-1-azabicyclo[2.2.2]- octane. Methods
similar to those described by A. D. Yanina et al., Khim. -Farm. Zh.
21(7):808-811 (1987) can be used. The isomeric compounds,
2-[(2-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane and
2-[(4-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared
in a similar manner by replacing 3-bromobenzaldehyde with
2-bromobenzaldehyde and 4-bromobenzaldehyde, respectively in the
above synthetic approach. Alternatively,
2-[(3-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared
form the previously described 2-[(3-aminophenyl)methyl]-1-azabic-
yclo[2.2.2]octane by conversion to the intermediate diazonium salt
compound using sodium nitrite and acid at 0.degree. C., followed by
treatment with cuprous bromide under Sandmeyer reaction conditions.
In a similar manner,
2-[(2-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane and
2-[(4-bromophenyl)methyl]-1-azabicyclo[2.2.2]octane can be prepared
from the corresponding amino compounds.
[0132] Compounds of the present invention may contain more than one
carbon between the aromatic ring and azabicyclic ring
functionalities. The manner in which such compounds as
2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2- .2]octane,
2-(2-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane, and
2-(2-(3-pyridyl)butyl)-1-azabicyclo[2.2.2]octane of the present
invention can be prepared can vary. For example,
2-(2-(3-pyridyl)ethyl)-1-azabicycl- o[2.2.2]octane can be prepared
by different methods. In one approach, 3-pyridineacetaldehyde (also
known as 2-(3-pyridyl)ethanal) can be condensed with
3-quinuclidinone hydrochloride (commercially available from Aldrich
Chemical Company) in a directed aldol reaction using a base such as
potassium hydroxide or sodium hydroxide in methanol or sodium
ethoxide in ethanol to afford
2-(2-(3-pyridyl)ethylene)-1-azabicyclo[2.2.- 2]octan-3-one. Aldol
condensations between an aldehyde and a ketone with accompanying
reaction modifications similar to those described by J. March,
Advanced Organic Chemistry, Reactions, Mechanisms, and Structure,
2.sup.nd edition, pp.849-853 (1977) can be used to give a mixture
of products. The carbon-carbon double bond of the resulting
unsaturated ketone can be reduced by hydrogenation using palladium
on charcoal to give the ketone,
242-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-one, which can be
further reduced under Wolff-Kishner conditions to yield
2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octane. Methods similar
to those described by A. D. Yanina et al., Khim.-Farm. Zh. 21(7):
808-811 (1987) can be used for the latter reductions.
Alternatively, in another synthetic method, the carbonyl group of
the above aldol product,
2-(2-(3-pyridyl)ethylene)-1-azabicyclo[2.2.2]octan-3-one can be
reduced by treatment with sodium borohydride in methanol to give
the alcohol,
2-(2-(3-pyridyl)ethylene)-1-azabicyclo[2.2.2]octan-3-ol. This
alcohol can be converted to the chloro intermediate,
3-chloro-2-(2-(3-pyridyl)ethylen- e)-1-azabicyclo[2.2.2]octane
dihydrochloride upon treatment with thionyl chloride.
Dechlorination can then be accomplished by hydrogenation with Raney
nickel to afford
2-(2-(3-pyridyl)ethylene)-1-azabicyclo[2.2.2]octan- e
dihydrochloride. The carbon-carbon double bond of the latter
compound can then be reduced by hydrogenation over 10% palladium on
charcoal in methanol to yield
2-(2-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octane
dihydrochloride.
[0133] Related compounds of the present invention such as
2-(243-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-one can be
prepared by reduction of the carbon-carbon double bond of the aldol
reaction product,
2-(2-(3-pyridyl)ethylene)-1-azabicyclo[2.2.2]octan-3-one by
hydrogenation over 10% palladium on charcoal in methanol. Also,
2-(2-(3-pyridyl)ethylen- e)-1-azabicyclo[2.2.2]octan-3-ol can be
prepared by reducing the ketone functionality of
242-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octan-3-one with sodium
borohydride in methanol. The latter alcohol can also be prepared by
the hydrogenation of 2-(243-pyridyl)ethylene)-1-azabicyclo[2.-
2.2]octan-3-one over Raney nickel in methanol.
[0134] Replacement of 2-(3-pyridyl)ethanal in the above synthetic
approach with 2-(3-pyridyl)propanal leads to the following
compounds: 2-(1-methyl-3-(3-pyridyl)propylene)-1-azabicyclo
[2.2.2]octan-3-one,
2-(3-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octan-3-one,
2-(1-methyl-3-(3-pyridyl)propylene)-1-azabicyclo[2.2.2]octan-3-ol,
3-chloro-2-(1-methyl-3-(3-pyridyl)propylene)-1-azabicyclo[2.2.2]octane
dihydrochloride,
2-(1-methyl-3-(3-pyridyl)propylene)-1-azabicyclo[2.2.2]o- ctane
dihydrochloride, and
2-(3-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octa- ne. Also,
2-(3-(3-pyridyl)propyl)-1-azabicyclo [2.2.2]octan-3-one, and
2-(3-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octan-3-ol can be
prepared by the previously described methods.
[0135] Replacement of 2-(3-pyridyl)ethanal in the above synthetic
approach with 2-(3-pyridyl)butanal leads to the following
compounds:
2-(1-methyl-4-(3-pyridyl)butylene)-1-azabicyclo[2.2.2]octan-3-one,
2-(4-(3-pyridyl)butyl)-1-azabicyclo[2.2.2]octan-3-one,
2-(1-methyl-4-(3-pyridyl)butylene)-1-azabicyclo[2.2.2]octan-3-ol,
3-chloro-2-(1-methyl-4-(3-pyridyl)butylene)-1-azabicyclo[2.2.2]octane
dihydrochloride,
2-(1-methyl-4-(3-pyridyl)butylene)-1-azabicyclo[2.2.2]oc- tane
dihydrochloride, and
2-(4-(3-pyridyl)butyl)-1-azabicyclo[2.2.2]octane- . Also,
2-(4(3-pyridyl)butyl)-1-azabicyclo[2.2.2]octan-3-one, and
2-(4-(3-pyridyl)butyl)-1-azabicyclo[2.2.2]octan-3-ol can be
prepared by the previously described methods.
[0136] The requisite aldehyde for the above aldol condensation,
3-pyridineacetaldehyde (also known as 2-(3-pyridyl)ethanal) can be
prepared by a number of synthetic methods. In one approach
3-pyridylacetic acid hydrochloride (commercially available from
Aldrich Chemical Company and Lancaster Synthesis, Inc.) can be
treated with trimethylsilyl chloride and triethylamine. The
resulting trimethylsilyl ester can then be reduced with
diisobutylaluminum hydride according to the method of S.
Chandrasekhar et al., Tetrahedron Lett. 39: 909-910 (1998).
Alternatively, 3-pyridineacetaldehyde can be prepared from
3-(3-pyridyl)acrylic acid (commercially available from Aldrich
Chemical Company and Lancaster Synthesis, Inc.) using the method of
D. H. Hey et al., J. Chem. Soc. Part 11: 1678-1683 (1950). In this
method, 3-(3-pyridyl)acrylic acid can be converted to its acid
chloride by treatment with thionyl chloride. Subsequent treatment
of the acid chloride with ammonia according to the method of L.
Panizza, Helv. Chim. Acta 24: 24E-28E (1941) yields
.beta.-(3-pyridyl)acrylamide. Hofmann rearrangement of the latter
amide by treatment with sodium hypochlorite affords methyl
2-(3-pyridyl)vinylcarbamate which can be hydrolyzed with refluxing
6N sulfuric acid in ethanol to give 3-pyridineacetaldehyde, which
can be isolated as its 2,4-dinitrophenylhydrazone sulfate.
[0137] The aldehyde, 3-(3-pyridyl)propanal required for the
preparation of 2-(3-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane
and related compounds can be prepared from 3-(3-pyridyl)propanol
(commercially available from Aldrich Chemical Company and Lancaster
Synthesis, Inc.). Oxidation of the latter alcohol with lead acetate
in pyridine according to the method of S. J. Ratcliffe et al., J.
Chem. Soc., Perkin Trans. 1 Issue 8: 1767-1771 (1985) affords
3-(3-pyridyl)propanal. Alternatively, 3-(3-pyridyl)propanal can be
prepared by Swern oxidation of 3-(3-pyridyl)propanol using oxalyl
chloride in dimethyl sulfoxide and dichloromethane according to the
methods of M. J. Stocks et al., Tetrahedron Lett. 36(36): 6555-6558
(1995) and A. J. Mancuso et al., J. Org. Chem. 44(23): 4148-4150
(1979).
[0138] The aldehyde, 3-(3-pyridyl)butanal required for the
preparation of 2-(4-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane
and related compounds can be prepared from 3-(3-pyridyl)propanol
(commercially available from Aldrich Chemical Company and Lancaster
Synthesis, Inc.) by a homologative process according to the method
of G. Solladi et al., Tetrahedron:Asymmetry 8(5): 801-810 (1997).
Treatment of 3-(3-pyridyl)propanol with tribromoimidazole and
triphenylphosphine yields 1-bromo-3-(3-pyridyl)propane, which can
be condensed with the lithium salt of 1,3-dithiane. Removal of the
dithianyl group of the resulting compound with aqueous mercuric
chloride and mercuric oxide affords 4-(3-pyridyl)butanal.
[0139] The manner in which
2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2- .2.2]octanes,
2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octanes and
2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octanes of the
present invention can be synthetically produced can vary. For
example, pyridine-3-carboxaldehyde and quinuclidin-3-one
hydrochloride (commercially available from Aldrich) are reacted
together in the presence of methanolic potassium hydroxide as
described in Neilsen and Houlihan, Org. React. 16: 1-438 (1968) to
give the aldol condensation product,
2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one as a
crystalline solid.
2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one can then be
converted to 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.-
2.2]octane-3-one by treatment with phenylmagnesium bromide in
ethanol at -10.degree. C. The ketone is then treated with sodium
borohydride to yield the alcohol,
2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]oc- tan-3-ol.
This intermediate is reacted with neat thionyl chloride at room
temperature to give
3-chloro-2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicycl-
o[2.2.2]octane as a crystalline solid. Removal of the chlorine is
accomplished by hydrogenation in the presence of Raney nickel as
described by de Koning, Org. Prep. Proced. Int. 7: 31 (1975) to
give the desired product,
2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octa- ne. The
related compounds, 2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.-
2.2]octane and
2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane can be
prepared in a similar manner by replacing phenylmagnesium bromide
with benzylmagnesium bromide or 2-phenethylmagnesium bromide,
respectively, in the synthetic approach given above.
[0140] The manner in which 2-(3-(4-, 5-, and
6-substituted)pyridylmethyl)-- 1-azabicyclo[2.2.2]oct-2-enes of the
present invention can be synthesized can vary. For example,
5-bromopyridine-3-carboxaldehyde and quinuclidin-3-one
hydrochloride (commercially available from Aldrich) are reacted
together in the presence of methanolic potassium hydroxide as
described in Neilsen and Houlihan, Org. React. 16: 1-438 (1968).
This aldol condensation product,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[- 2.2.2]octan-3-one,
is then dissolved in ethanol and hydrogenated with 5% palladium on
charcoal to afford 2-(3-(5-bromo)pyridylmethyl)-1-azabicyclo-
[2.2.2]octan-3-one. Reaction conditions are controlled to avoid
removal of the bromine substituent. Treatment with sodium
borohydride gives the alcohol,
2-(3-(5-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. This
intermediate is reacted with neat thionyl chloride at room
temperature to give
3-chloro-2-(3-(5-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]octane.
Elimination of the aliphatic chloro moiety is accomplished by
treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene, according to the
method of Wolkoff, J. Org. Chem. 47: 1944-1946 (1982), to give the
desired product,
2-(3-(5-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]oct-2-ene. The
isomeric compounds, 2-(3-(4-bromo)pyridylmethyl)-1-azabicyclo
[2.2.2]oct-2-ene and
2-(3-(6-bromo)pyridylmethyl)-1-azabicyclo[2.2.2]oct-2-ene can be
prepared in a similar manner by replacing
5-bromopyridine-3-carboxaldehyde with
4-bromopyridine-3-carboxaldehyde or
6-bromopyridine-3-carboxaldehyde, respectively, in the synthetic
approach given above.
[0141] The manner in which
3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[- 2.2.2]octane of
the present invention is synthesized can vary. For example,
pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride
(commercially available from Aldrich) are reacted together in the
presence of methanolic potassium hydroxide as described in Neilsen
and Houlihan, Org. React. 16: 1-438 (1968). This aldol condensation
product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one, is
then dissolved in methanol and hydrogenated in the presence of
Raney nickel catalyst to afford
2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. This alcohol is
then etherified with phenol via Mitsunobu coupling with
diethylazidocarboxylate and triphenylphosphine, as described by
Guthrie et al., J. Chem. Soc., Perkin Trans I 45: 2328 (1981), to
afford the desired product,
3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]oct- ane.
[0142] The manner in which 3-(phenylmethoxy and
2-phenylethoxy)-243-pyridy- lmethyl)-1-azabicyclo[2.2.2]octanes of
the present invention are synthesized can vary. For example,
pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride
(commercially available from Aldrich) are reacted together in the
presence of methanolic potassium hydroxide as described in Neilsen
and Houlihan, Org. React. 16: 1-438 (1968). This aldol condensation
product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]oct- an-3-one,
is then dissolved in methanol and hydrogenated in the presence of
Raney nickel catalyst to afford
2-(3-pyridylmethyl)-1-azabicyclo[2.2.2- ]octan-3-ol. Treatment of
the alcohol with sodium hydride followed by benzyl bromide in a
suitable solvent affords the desired product,
3-(phenylmethoxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane.
3-(2-Phenylethoxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane
can be synthesized by substituting benzyl bromide with
2-bromoethylbenzene.
[0143] The manner in which 2-(3-(4-, 5-, and
6-substituted)pyridylmethyl)-- 1-azabicyclo[2.2.1]heptanes of the
present invention can be synthesized can vary. For example,
5-bromopyridine-3-carboxaldehyde and
1-azabicyclo[2.2.1]heptan-3-one, which is itself synthesized
according to the method of Wadsworth et al., U.S. Pat. No.
5,217,975, are reacted together in the presence of methanolic
potassium hydroxide as described in Neilsen and Houlihan, Org.
React. 16: 1-438 (1968). This aldol condensation product,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.1]- heptan-3-one,
is then treated with sodium borohydride to yield the alcohol,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.1]heptan-3-ol as a
crystalline solid. This intermediate is reacted with neat thionyl
chloride at room temperature to give
3-chloro-2-(3-(5-bromo)pyridylmethyl-
ene)-1-azabicyclo[2.2.1]heptane. Reductive removal of the chlorine
is accomplished by lithium trimethoxyaluminum hydride and copper
iodide as described by Masamune et al., J. Am. Chem. Soc. 95: 6452
(1973) to give the desired product,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[2.2.1]h- eptane, as a
crystalline solid. This methylene intermediate can the be converted
to the desired product, 2-(3-(5-bromo)pyridylmethyl)-1-azabicyc-
lo[2.2.1]heptane, by hydrogenation in the presence of palladium on
charcoal catalyst. Reaction conditions are controlled to avoid
removal of the bromine subtituent. The isomeric compounds, 2-(3-(4
bromo)pyridylmethyl)-1-azabicyclo[2.2.1]heptane and
2-(3-(6-bromo)pyridylmethyl)-1-azabicyclo[2.2.1]heptane can be
prepared in a similar manner by replacing
5-bromopyridine-3-carboxaldehyde with
4-bromopyridine-3-carboxaldehyde or
6-bromopyridine-3-carboxaldehyde, respectively, in the synthetic
approach given above.
[0144] The manner in which 2-(3-(4-, 5-, and
6-substituted)pyridylmethyl)-- 1-azabicyclo[3.2.1]octanes of the
present invention can be synthesized can vary. For example,
5-bromopyridine-3-carboxaldehyde and
1-azabicyclo[3.2.1]octan-3-one, which is itself synthesized
according to the method of Thill and Aaron J. Org. Chem. 33:
4376-4379 (1969), are reacted together in the presence of
methanolic potassium hydroxide as described in Neilsen and
Houlihan, Org. React. 16: 1-438 (1968). The Aldol condensation
products, 2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo-
[3.2.1]octan-3-one and
4-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[3.2.1]- octan-3-one
are then chromatographically separated. The desired
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[3.2.1]octan-3-one, is
then treated with sodium borohydride to yield the alcohol,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[3.2.1]octan-3-ol as a
crystalline solid. This intermediate is reacted with neat thionyl
chloride at room temperature to give
3-chloro-2-(3-(5-bromo)pyridylmethyl-
ene)-1-azabicyclo[3.2.1]octane dihydrochloride. Reductive removal
of the chlorine is accomplished by lithium trimethoxyaluminum
hydride and copper iodide as described by Masamune et al., J. Am.
Chem. Soc. 95: 6452 (1973) to give,
2-(3-(5-bromo)pyridylmethylene)-1-azabicyclo[3.2.1]octane, as a
crystalline solid. This methylene intermediate can then be
converted to the final product,
2-(3-(5-bromo)pyridylmethyl)-1-azabicyclo[3.2.1]octane- , by
hydrogenation in the presence of palladium on charcoal catalyst.
The isomeric compounds,
2-(3-(4-bromo)pyridylmethyl)-1-azabicyclo[3.2.1]octan- e and
2-(3-(6-bromo)pyridylmethyl)-1-azabicyclo[3.2.1]octane can be
prepared in a similar manner by replacing
5-bromopyridine-3-carboxaldehyd- e with
4-bromopyridine-3-carboxaldehyde or
6-bromopyridine-3-carboxaldehyd- e, respectively, in the synthetic
approach given above.
[0145] The manner in which
2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.- 2]octane and other
analogous compounds possessing substituents at the C-5 position of
the pyridine ring are synthesized can vary. In another example,
2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane can be
prepared starting with the aldol condensation of
5-bromo-3-pyridinecarbox- aldehyde and 3-quinuclidinone
hydrochloride (commercially available from Aldrich Chemical
Company) which proceeds in 75% yield using potassium hydroxide in
methanol. The carbon-carbon double bond of the resulting
2-((5-bromo-3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one can
be selectively reduced with an appropriate reducing agent, such as
lithium tri-sec-butylborohydride (L-Selectride.RTM.) or potassium
tri-sec-butylborohydride (K-Selectride.RTM.) (available from
Aldrich Chemical Company) in tetrahydrofuran at -78.degree. C.
using methodology described by J. M. Fortunato et al., J. Org.
Chem. 41(12): 2194-2200 (1976) or with sodium borohydride modified
with nickel(II) chloride hexahydrate in an ethanolic or aqueous
solution to give
2-((5-bromo-3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one. The
latter ketone can be reduced under Wolff-Kishner conditions with
hydrazine and base (or under modified Wolff-Kishner conditions with
tosylhydrazine and sodium cyanoborohydride) to yield
2-((5-bromo-3-pyridyl)methyl)-1-azabicy- clo[2.2.2]octane.
[0146] A number of compounds possessing substituents at the C-5
position of the pyridine ring can be prepared from
2-((5-bromo-3-pyridyl)methyl)-1- -azabicyclo[2.2.2]octane. For
example, the 5-amino-substituted compound can be prepared from the
corresponding 5-bromo compound using ammonia in the presence of a
copper catalyst according to the general method of C. Zwart et al.,
Recueil Trav. Chim. Pays-Bas 74: 1062-1069 (1955). 5-Alkylamino
substituted compounds can be prepared in a similar manner. 5-Alkoxy
substituted analogs can be prepared from the corresponding 5-bromo
compounds by heating with a sodium alkoxide in
N,N-dimethylformamide or by use of a copper catalyst according to
the general techniques described in D. L. Comins et al., J. Org.
Chem. 55: 69-73 (1990) and H. J. den Hertog et al., Recl. Trav.
Chim. Pays-Bas 74: 1171-1178 (1955). 5-Ethynyl-substituted
compounds can be prepared from the appropriate 5-bromo compounds by
palladium catalyzed coupling using 2-methyl-3-butyn-2-ol, followed
by base (sodium hydride) catalyzed deprotection according to the
general techniques described in N. D. P. Cosford et al., J. Med.
Chem. 39: 3235-3237 (1996). The 5-ethynyl analogs can be converted
into the corresponding 5-ethenyl, and subsequently to the
corresponding 5-ethyl analogs by successive catalytic hydrogenation
reactions. The 5-azido substituted analogs can be prepared from the
corresponding 5-bromo compounds by reaction with lithium azide in
N,N-dimethylformamide. 5-Alkylthio substituted analogs can be
prepared from the corresponding 5-bromo compound by reaction with
an appropriate alkylmercaptan in the presence of sodium using
techniques known to those skilled in the art of organic
synthesis.
[0147] A number of 5-substituted analogs of the aforementioned
compounds can be synthesized from the corresponding 5-amino
compounds via the 5-diazonium salt intermediates. Among the other
5-substituted analogs that can be produced from 5-diazonium salt
intermediates are: 5-hydroxy analogs, 5-fluoro analogs, 5-chloro
analogs, 5-bromo analogs, 5-iodo analogs, 5-cyano analogs, and
5-mercapto analogs. These compounds can be synthesized using the
general techniques set forth in C. Zwart et al., supra. For
example, 5-hydroxy substituted analogs can be prepared from the
reaction of the corresponding 5-diazonium salt intermediates with
water. 5-Fluoro substituted analogs can be prepared from the
reaction of the 5-diazonium salt intermediates with fluoroboric
acid. 5-Chloro substituted analogs can be prepared from the
reaction of the 5-amino compounds with sodium nitrite and
hydrochloric acid in the presence of copper chloride. 5-Cyano
substituted analogs can be prepared from the reaction of the
corresponding 5-diazonium salt intermediates with potassium copper
cyanide. 5-Amino substituted analogs can also be converted to the
corresponding 5-nitro analogs by reaction with fuming sulfuric acid
and peroxide, according to the general techniques described in Y.
Morisawa, J. Med. Chem. 20: 129-133 (1977) for converting an
aminopyridine to a nitropyridine. Appropriate 5-diazonium salt
intermediates can also be used for the synthesis of mercapto
substituted analogs using the general techniques described in J. M.
Hoffman et al., J. Med. Chem. 36: 953-966 (1993). The 5-mercapto
substituted analogs can in turn be converted to the 5-alkylthio
substituted analogs by reaction with sodium hydride and an
appropriate alkyl bromide. 5-Acylamido analogs of the
aforementioned compounds can be prepared by reaction of the
corresponding 5-amino compounds with an appropriate acid anhydride
or acid chloride using techniques known to those skilled in the art
of organic synthesis.
[0148] 5-Hydroxy substituted analogs of the aforementioned
compounds can be used to prepare corresponding 5-alkanoyloxy
substituted compounds by reaction with the appropriate acid, acid
chloride, or acid anhydride. 5-Cyano substituted analogs of the
aforementioned compounds can be hydrolyzed to afford the
corresponding 5-carboxamido substituted compounds. Further
hydrolysis results in formation of the corresponding 5-carboxylic
acid substituted analogs. Reduction of the 5-cyano substituted
analogs with lithium aluminum hydride yields the corresponding
5-aminomethyl analogs. 5-Acyl substituted analogs can be prepared
from corresponding 5-carboxylic acid substituted analogs by
reaction with an appropriate alkyl lithium using techniques known
to those skilled in the art.
[0149] 5-Carboxylic acid substituted analogs of the aforementioned
compounds can be converted to the corresponding esters by reaction
with an appropriate alcohol and acid catalyst. Compounds with an
ester group at the 5-pyridyl position can be reduced with sodium
borohydride or lithium aluminum hydride to produce the
corresponding 5-hydroxyalkyl (e.g., 5-hydroxymethyl) substituted
analogs. These analogs in turn can be converted to compounds
bearing an ether moiety at the 5-pyridyl position by reaction with
sodium hydride and an appropriate alkyl halide, using conventional
techniques. Alternatively, the 5-hydroxymethyl substituted analogs
can be reacted with tosyl chloride to provide the corresponding
5-tosyloxymethyl analogs. The 5-carboxylic acid substituted analogs
can also be converted to the corresponding 5-alkylaminoacyl analogs
by reaction with an appropriate alkylamine and thionyl chloride.
5-Acyl substituted analogs of the aforementioned compounds can be
prepared from the reaction of the appropriate 5-carboxylic acid
substituted compounds with an appropriate alkyl lithium salt, using
techniques known to those skilled in the art of organic
synthesis.
[0150] 5-Tosyloxymethyl substituted analogs of the aforementioned
compounds can be converted to the corresponding 5-methyl
substituted compounds by reduction with lithium aluminum hydride.
5-Tosyloxymethyl substituted analogs of the aforementioned
compounds can also be used to produce 5-alkyl substituted compounds
via reaction with an alkyl lithium salt. 5-Hydroxy substituted
analogs of the aforementioned compounds can be used to prepare
5-N-alkylcarbamoyloxy substituted compounds by reaction with
N-alkylisocyanates. 5-Amino substituted analogs of the
aforementioned compounds can be used to prepare
5-N-alkoxycarboxamido substituted compounds by reaction with alkyl
chloroformate esters, using techniques known to those skilled in
the art of organic synthesis. Analogous chemistries to those
described hereinbefore, for the preparation of the 5-substituted
analogs of the azabicyclo analogs, can be devised for the synthesis
of 2-, 4-, and 6-substituted analogs. For example, a number of 2-,
4, and 6-aminopyridyl azabicyclo compounds can be converted to the
corresponding diazonium salt intermediates, which can be
transformed to a variety of compounds with substituents at the 2-,
4-, and 6-positions of the pyridine ring as was described for the
5-substituted analogs above.
[0151] The present invention relates to nicotinic antagonists. The
present invention also relates to methods for providing prevention
or treatment of conditions or disorders in a subject susceptible to
such a condition or disorder, and for providing treatment to a
subject suffering from a condition or disorder. For example, the
method comprises administering to a patient an amount of a compound
effective for providing some degree of prevention of the
progression of a disorder such as a CNS disorder (i.e., provide
protective effects), amelioration of the symptoms of the disorder,
and/or amelioration of the reoccurrence of the disorder. In
particular, the methods of the present invention comprise
administering to a patient in need thereof, an amount of a compound
selected from the group of compounds of general formulae set forth
hereinbefore, which amount is effective to prevent or treat the
condition or disorder affecting the patient. The present invention
further relates to pharmaceutical compositions incorporating the
compounds of general formulae set forth hereinbefore.
[0152] The compounds can be employed in a free base form or in a
salt form (e.g., as pharmaceutically acceptable salts). Examples of
suitable pharmaceutically acceptable salts include inorganic acid
addition salts such as hydrochloride, hydrobromide, sulfate,
phosphate, and nitrate; organic acid addition salts such as
acetate, galactarate, propionate, succinate, lactate, glycolate,
malate, tartrate, citrate, maleate, fumarate, methanesulfonate,
salicylate, p-toluenesulfonate, benzoate, benzene sulfonoate, and
ascorbate; salts with acidic amino acids such as aspartate and
glutamate; alkali metal salts such as sodium salt and potassium
salt; alkaline earth metal salts such as magnesium salt and calcium
salt; ammonium salt; organic basic salts such as trimethylamine
salt, triethylamine salt, pyridine salt, picoline salt,
dicyclohexylamine salt, and N,N-dibenzylethylenediamine salt; and
salts with basic amino acids such as the lysine salt and arginine
salts. The salts may in some cases be hydrates or ethanol
solvates.
[0153] The compounds of the present invention are beneficial in
therapeutic applications requiring a selective inhibition at
certain nicotinic receptor subtypes; that is, the compounds are
antagonists at certain nicotinic receptor subtypes. The
pharmaceutical compositions of the present invention are useful for
the prevention and treatment of a wide variety of conditions or
disorders. The compounds of the present invention are useful for
treating certain CNS conditions and disorders; such as in providing
neuroprotection, in treating patients susceptible to convulsions,
in treating depression, in treating autism, in treating Tourette's
syndrome, in treating certain neuroendocrine disorders, and in the
management of stroke. The compounds of the present invention also
are useful in treating hypertension, for effecting weight loss, in
treating type II diabetes and neoplasia, or as antibacterial or
antiviral agents. The compounds of the present invention also are
useful, when appropriately radio-labeled, as probes in life science
applications (e.g., as selective probes in neuroimaging
applications). For example, compounds of the present invention can
be used to inhibit interaction of viral proteins with nicotinic
receptors. See, Bracci et al., FEBS Letters. 311(2): 115-118
(1992). See also, for example, the types of conditions and
disorders that are treated using nicotinic compounds, as set forth
in PCT WO 94/08992 and PCT WO 96/31475, U.S. Pat. Nos. 5,583,140 to
Bencherif et al., 5,597,919 to Dull et al. and 5,604,231 to Smith
et al., and U.S. patent application Ser. No. 09/054,175, filed Apr.
2, 1998.
[0154] The pharmaceutical compositions of the present invention can
also include various other components as additives or adjuncts.
Exemplary pharmaceutically acceptable components or adjuncts which
are employed in relevant circumstances include antioxidants, free
radical scavenging agents, peptides, growth factors, antibiotics,
bacteriostatic agents, immunosuppressives, buffering agents,
anti-inflammatory agents, anti-pyretics, time release binders,
anaesthetics, steroids and corticosteroids. Such components can
provide additional therapeutic benefit, act to affect the
therapeutic action of the pharmaceutical composition, or act
towards preventing any potential side effects which may be posed as
a result of administration of the pharmaceutical composition. In
certain circumstances, a compound of the present invention can be
employed as part of a pharmaceutical composition with other
compounds intended to prevent or treat a particular disorder.
[0155] The manner in which the compounds are administered can vary.
The compounds can be administered by inhalation (e.g., in the form
of an aerosol either nasally or using delivery articles of the type
set forth in U.S. Pat. No. 4,922,901 to Brooks et al., the
disclosure of which is incorporated herein by reference in its
entirety); topically (e.g., in lotion form); orally (e.g., in
liquid form within a solvent such as an aqueous or non-aqueous
liquid, or within a solid carrier); intravenously (e.g., within a
dextrose or saline solution); as an infusion or injection (e.g., as
a suspension or as an emulsion in a pharmaceutically acceptable
liquid or mixture of liquids); intrathecally; opthamalically,
intracerebro ventricularly; or transdermally (e.g., using a
transdermal patch). Although it is possible to administer the
compounds in the form of a bulk active chemical, it is preferred to
present each compound in the form of a pharmaceutical composition
or formulation for efficient and effective administration.
Exemplary methods for administering such compounds will be apparent
to the skilled artisan. For example, the compounds can be
administered in the form of a tablet, a hard gelatin capsule or as
a time release capsule. As another example, the compounds can be
delivered transdermally using the types of patch technologies
available from Novartis and Alza Corporation. The administration of
the pharmaceutical compositions of the present invention can be
intermittent, or at a gradual, continuous, constant or controlled
rate to a warm-blooded animal, (e.g., a mammal such as a mouse,
rat, cat, rabbit, dog, pig, cow, or monkey); but advantageously is
preferably administered to a human being. In addition, the time of
day and the number of times per day that the pharmaceutical
formulation is administered can vary. Administration preferably is
such that the active ingredients of the pharmaceutical formulation
interact with receptor sites within the body of the subject that
effect the functioning of the CNS. More specifically, in treating a
CNS disorder administration preferably is such so as to optimize
the effect upon those relevant receptor subtypes (e.g., those which
have an effect upon the functioning of the CNS), while minimizing
the effects upon receptor subtypes in muscle and ganglia. Other
suitable methods for administering the compounds of the present
invention are described in U.S. Pat. No. 5,604,231 to Smith et al.,
the disclosure of which is incorporated herein by reference in its
entirety.
[0156] Compounds of the present invention bind to relevant
receptors and, are antagonists (i.e., inhibit the function of
relevant receptor subtypes). Concentrations, determined as the
amount of compound per volume of receptor-containing tissue,
typically provide a measure of the degree to which that compound
binds to and affects relevant receptor subtypes. The compounds of
the present invention are selective in that at relevant
concentrations (i.e., low concentrations) those compounds bind to,
and have inhibitory effects upon, receptors associated with the
modulation of neurotransmitters.
[0157] The compounds useful according to the method of the present
invention have the ability to pass across the blood-brain barrier
of the patient. As such, such compounds have the ability to enter
the central nervous system of the patient. The log P values of
typical compounds, which are useful in carrying out the present
invention are generally greater than about 0, often are greater
than about 0.5, and frequently are greater than about 1.5. The log
P values of such typical compounds generally are less than about 4,
often are less than about 3.5, and frequently are less than about
3.0. Log P values provide a measure of the ability of a compound to
pass across a diffusion barrier, such as a biological membrane.
See, Hansch, et al., J. Med. Chem. 11:1 (1968).
[0158] The compounds useful according to the method of the present
invention have the ability to bind to, and in most circumstances,
cause inhibition of, nicotinic receptors of the brain of the
patient. As such, these compounds have the ability to express
nicotinic pharmacology, and in particular, to act as nicotinic
antagonists. The receptor binding constants of typical compounds
useful in carrying out the present invention generally exceed about
500 nM, often exceed about 100 nM, and frequently exceed about 50
nM. The receptor binding constants of such typical compounds
generally are less than about 1 uM, often are less than about 100
nM, and frequently are less than about 20 nM. Receptor binding
constants provide a measure of the ability of the compound to bind
to half of the relevant receptor sites of certain brain cells of
the patient. See, Cheng, et al., Biochem. Pharmacol. 22:3099
(1973).
[0159] The appropriate dose of the compound is that amount
effective to prevent occurrence of the symptoms of the condition or
disorder, or to treat some symptoms of the condition or disorder
from which the patient suffers. By "effective amount", "therapeutic
amount" or "effective dose" is meant that amount sufficient to
elicit the desired pharmacological or therapeutic effects, thus
resulting in effective prevention or treatment of the condition or
disorder. Thus, when treating a CNS disorder, an effective amount
of compound is an amount sufficient to pass across the blood-brain
barrier of the subject, to bind to relevant receptor sites in the
brain of the subject, and to inhibit relevant nicotinic receptor
subtypes (e.g., inhibits neurotransmitter secretion, thus resulting
in effective prevention or treatment of the disorder). Prevention
of the condition or disorder is manifested by delaying the onset of
the symptoms of the condition or disorder. Treatment of the
condition or disorder is manifested by a decrease in the symptoms
associated with the condition or disorder, or an amelioration of
the reoccurrence of the symptoms of the condition or disorder.
[0160] The effective dose can vary, depending upon factors such as
the condition of the patient, the severity of the symptoms of the
disorder, and the manner in which the pharmaceutical composition is
administered. For human patients, the effective dose of typical
compounds generally requires administering the compound in an
amount sufficient to inhibit relevant receptors to effect
neurotransmitter release but the amount should be insufficient to
induce effects on skeletal muscles and ganglia to any significant
degree. The effective dose of compounds will of course differ from
patient to patient but in general includes amounts starting where
desired therapeutic effects are observed but below the amounts
where muscular effects are observed.
[0161] Typically, the effective dose of compounds generally
requires administering the compound in an amount of less than 1
ug/kg of patient weight. Often, the compounds of the present
invention are administered in an amount from 10 ng to less than 1
ug/kg of patient weight, frequently between about 0.1 ug to less
than 1 ug/kg of patient weight, and preferably between about 0.1 ug
to about 0.5 ug/kg of patient weight. Compounds of the present
invention can be administered in an amount of 0.3 to 0.5 ug/kg of
patient weight. For compounds of the present invention that do not
induce effects on muscle or ganglion-type nicotinic receptors at
low concentrations, the effective dose is less than 50 ug/kg of
patient weight; and often such compounds are administered in an
amount from 0.5 ug to less than 50 ug/kg of patient weight. The
foregoing effective doses typically represent that amount
administered as a single dose, or as one or more doses administered
over a 24 hour period.
[0162] For human patients, the effective dose of typical compounds
generally requires administering the compound in an amount of at
least about 1, often at least about 10, and frequently at least
about 25 ug/24 hr./patient. For human patients, the effective dose
of typical compounds requires administering the compound which
generally does not exceed about 500, often does not exceed about
400, and frequently does not exceed about 300 ug/24 hr./patient. In
addition, administration of the effective dose is such that the
concentration of the compound within the plasma of the patient
normally does not exceed 500 ng/ml, and frequently does not exceed
100 ng/ml.
[0163] The compounds useful according to the method of the present
invention have the ability to demonstrate a nicotinic function by
effectively inhibiting neurotransmitter secretion from nerve ending
preparations (i.e., synaptosomes). As such, such compounds have the
ability to inhibit relevant neurons to release or secrete
acetylcholine, dopamine, and other neurotransmitters. Generally,
typical compounds useful in carrying out the present invention
provide for the inhibition of dopamine secretion in amounts of at
least one third, typically at least about 10 times less, frequently
at least about 100 times less, and sometimes at least about 1,000
times less, than those required for activation of muscle or
ganglion-type nicotinic receptors.
[0164] The compounds of the present invention, when employed in
effective amounts in accordance with the method of the present
invention, are selective to certain relevant nicotinic receptors,
but do not cause significant activation of receptors associated
with undesirable side effects at concentrations at least 10 times
higher than those required for inhibition of dopamine release. By
this is meant that a particular dose of compound resulting in
prevention and/or treatment of a CNS disorder, is essentially
ineffective in eliciting activation of certain ganglionic-type
nicotinic receptors at concentration higher than 5 times,
preferably higher than 100 times, and more preferably higher than
1,000 times, than those required for inhibition of dopamine
release. This selectivity of certain compounds of the present
invention against those receptors responsible for cardiovascular
side effects is demonstrated by a lack of the ability of those
compounds to activate nicotinic function of adrenal chromaffin
tissue at concentrations at least 10 times greater than those
required for inhibition of dopamine release.
[0165] Compounds of the present invention, when employed in
effective amounts in accordance with the method of the present
invention, are effective towards providing some degree of
prevention of the progression of certain conditions and disorders,
amelioration of the symptoms of those conditions and disorders, an
amelioration to some degree of the reoccurrence of those conditions
and disorders. However, such effective amounts of those compounds
are not sufficient to elicit any appreciable side effects, as
demonstrated by increased effects relating to the cardiovascular
system, and effects to skeletal muscle. As such, administration of
certain compounds of the present invention provides a therapeutic
window in which treatment of certain conditions and disorders is
provided, and side effects are avoided. That is, an effective dose
of a compound of the present invention is sufficient to provide the
desired effects upon relevant nicotinic receptor subtypes, but is
insufficient (i.e., is not at a high enough level) to provide
undesirable side effects. Preferably, effective administration of a
compound of the present invention resulting in treatment of a wide
variety of conditions and disorders occurs upon administration of
less than 1/5, and often less than {fraction (1/10)} that amount
sufficient to cause any side effects to a significant degree.
[0166] The following examples are provided to further illustrate
the present invention, and should not be construed as limiting
thereof.
EXAMPLE 1
[0167] Determination of Binding to Relevant Receptor Sites
[0168] Binding of the compounds to relevant receptor sites was
determined in accordance with the techniques described in U.S. Pat.
No. 5,597,919 to Dull et al. Inhibition constants (Ki values),
reported in nM, were calculated from the IC.sub.50 values using the
method of Cheng et al., Biochem, Pharmacol. 22:3099 (1973).
EXAMPLE 2
[0169] Determination of Binding to Alpha 7 type Receptor Sites
[0170] Sprague-Dawley rats were purchased from The Harlan Co.
(Indiana, U.S.A.) and maintained on a 12 hour light/dark cycle with
water and standard Purina Rat Chow ad libitum. Rats were sacrificed
using CO.sub.2 anesthesia followed by decapitation and hippocampi
were isolated and processed according to previously described
protocols (Bencherif et al., 1996). Cells were harvested in cold
Tris buffer (5 mM, pH 7.4), and homogenized with a Polytron
(Brinkmann Instruments, NY; settings at full power for 10 seconds).
The homogenate was centrifuged at 40,000.times.g for 10 minutes,
the supernatant was discarded, and the pellet was reconstituted in
PBS (pH 7.4). Standard procedures for ligand binding studies were
followed and sample aliquots were reserved for determination of
protein concentration with bovine serum albumin as the standard.
Equilibrium binding assays were conducted at room temperature by
incubating membrane aliquots suspended in 300 ul assay buffer with
10 nM .sup.1251-labeled monoiodinated .alpha.-bungarotoxin (1-Bgt)
(Dupont, NEN). Non-specific binding was determined in samples
supplemented with 10 uM nicotine or 1 mM carbachol. Incubation was
terminated by rapid filtration on a multimanifold tissue harvester
(Brandel) using G/C filters presoaked in 0.33% polyethyleneimine.
Samples were processed for specific radioligand binding assays
using .sup.125I-labelled monoiodinated .alpha.-bungarotoxin (1-Bgt)
obtained from New England Nuclear (NEN). Reagents were purchased
from Sigma Chemical Co. and were of the highest available grade.
Radiolabelled ligands were purchased from New England Nuclear
(NEN).
EXAMPLE 3
[0171] Determination of Receptor Activation/Inhibition and Dopamine
Release
[0172] Dopamine release was measured using the techniques described
in U.S. Pat. No. 5,597,919 to Dull et al. Release is expressed as a
percentage of release obtained with a concentration of
(S)-(-)-nicotine resulting in maximal effects. Reported EC.sub.50
values are expressed in nM, and E.sub.max values represent the
amount released relative to (S)-(-)-nicotine or tetramethylammonium
ion (TMA), on a percentage basis.
[0173] Isotopic rubidium release was measured using the techniques
described in Bencherif et al., JPET, 279: 1413-1421 (1996).
Reported EC.sub.50 values are expressed in nM, and E.sub.max values
represent the amount of rubidium ion released relative to 300 uM
tetramethylammonium ion, on a percentage basis.
[0174] Reported IC.sub.50 values are expressed in nM and represent
the concentration resulting in 50% inhibition of agonist induced
receptor activation. E.sub.max values represent the amount released
relative to (S)-(-)-nicotine on a percentage basis.
EXAMPLE 4
[0175] Determination of Dopamine Release
[0176] Dopamine release was measured using the techniques described
in U.S. Pat. No. 5,597,919 to Dull et al. Release is expressed as a
percentage of release obtained with a concentration of
(S)-(-)-nicotine resulting in maximal effects. Reported EC.sub.50
values are expressed in nM, and E.sub.max values represent the
amount released relative to (S)-(-)-nicotine on a percentage
basis.
EXAMPLE 5
[0177] Determination of Interaction with Muscle Receptors
[0178] The determination of the interaction of the compounds with
muscle receptors was carried out in accordance with the techniques
described in U.S. Pat. No. 5,597,919 to Dull et al. The maximal
activation for individual compounds (E.sub.max) was determined as a
percentage of the maximal activation induced by (S)-(-)-nicotine.
Reported E.sub.max values represent the amount released relative to
(S)-(-)-nicotine on a percentage basis.
EXAMPLE 6
[0179] Determination of Interaction with Ganglion Receptors
[0180] The determination of the interaction of the compounds with
ganglionic receptors was carried out in accordance with the
techniques described in U.S. Pat. No. 5,597,919 to Dull et al. The
maximal activation for individual compounds (E.sub.max) was
determined as a percentage of the maximal activation induced by
(S)-(-)-nicotine. Reported E.sub.max values represent the amount
released relative to (S)-(-)-nicotine on a percentage basis.
EXAMPLE 7
[0181] Determination of Log P Value
[0182] Log P values, which have been used to assess the relative
abilities of compounds to pass across the blood-brain barrier
(Hansch, et al., J. Med. Chem. ii: 1 (1968)), were calculated using
the Cerius.sup.2 software package Version 3.5 by Molecular
Simulations, Inc.
EXAMPLE 8
[0183] Sample No. 1 is
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane, which was prepared
in accordance with the following techniques:
[0184] Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and
powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were
dissolved in methanol (25 ml) and stirred for 15 mins.
Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one
portion and the mixture was stirred for an additional 20 hrs. The
reaction mixture was then diluted with 40 ml water and cooled to
0.degree. C. yielding 2-((3-pyridyl)methylene)-1-a-
zabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was
collected, washed with distilled water and dried under vacuum (5.16
g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one
(3 g, 14.0 mmol) was dissolved in 200 ml methanol and sodium
borohydride (3 g, 79.6 mmol) was added in portions (exothermic
reaction) with vigorous stirring. After 1 hr of continued stirring,
acetone (100 ml) was slowly added to neutralize the remaining
borohydride reagent. The mixture was evaporated to dryness and the
resulting residue suspended in water (200 ml) and extracted three
times with 200 ml portions of chloroform. The chloroform phases
were combined, dried over MgSO.sub.4, and rotary evaporated to give
a clear oil; crystallization of the free base gave a quantitative
yield of 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as
a white precipitate.
2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7
mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol)
under a nitrogen atmosphere at 0.degree. C., the reaction was than
brought to room temperature and stirred for one additional hour.
Rotary evaporation at 60.degree. C. produced a viscous oil which,
when suspended in ether, afforded
3-chloro-2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]o- ctane
dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). This
chloroquinuclidine (0.3 g, 15 mmol) was dissolved in ethanol (50
ml) and wet Rainey nickel (0.5 g) was carefully added under
nitrogen. The suspension was hydrogenated at 50 psig in a Parr
hydrogenation apparatus for 6 hrs followed by filtration through a
pad of Celite filter aid and additional washing of the pad with
methanol. Rotary evaporation of the pooled solvents gave
2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane as a clear oil
that solidified upon cooling (0.2 g, 70%). This material (120 mg)
was dissolved in 50 ml methanol followed by the careful addition of
0.1 g 10% palladium on charcoal. The suspension was hydrogenated at
50 psig in a Parr hydrogenation apparatus for 28 hrs followed by
filtration through a pad of Celite filter aid and additional
washing of the pad with methanol. Evaporation of the solvents
afforded a white residue which was crystallized from ethanol-ether
to give the desired material,
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane, as a white solid
(99 mg, 81%).
[0185] Sample No. 1 exhibits a log P of 1.99, and such a favorable
log P value indicates that the compound has the capability of
passing the blood-brain barrier. The compound exhibits a Ki of 37
nM at .alpha.4.beta.2 receptor subtypes and a Ki of 50 uM at
.alpha.7 receptor subtypes, indicating selectivity to each of those
receptor subtypes. The binding constant indicates that the compound
exhibits high affinity binding to certain relevant CNS nicotinic
receptors.
[0186] Sample No. 1 exhibits an E.sub.max value of 0% (at 100 uM)
for dopamine release. Sample No. 1 exhibits an E.sub.max value of
20% (at 100 uM) at muscle-type receptors, indicating that the
compound minimally induces activation of muscle-type receptors. The
sample exhibits an E.sub.max value of 78% (at 100 uM) at
ganglionic-type receptors.
EXAMPLE 9
[0187] Sample No. 2 is
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-on- e, which was
prepared in accordance with the following techniques:
[0188] Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and
powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were
dissolved in methanol (25 ml) and stirred for 15 mins.
Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one
portion and the mixture was stirred for an additional 20 hrs. The
reaction mixture was then diluted with 40 ml water and cooled to
0.degree. C. yielding 2-((3-pyridyl)methylene)-1-a-
zabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was
collected, washed with distilled water and dried under vacuum (5.16
g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one
(1.0 g, 4.7 mmol) was combined with 50 ml methanol and 0.2 g
palladium on charcoal (5% w/w) in a hydrogenation vessel.
Hydrogenation (50 psig) was carried out for 4 hrs., after which
time the slurry was carefully filtered through a pad of Celite
filter aid. Evaporation of solvent gave 2-((3-pyridyl)methyl)-1-az-
abicyclo[2.2.2]octan-3-one as white semisolid, which dissolved in
ethanol give a white crystalline solid upon cooling (0.82 g
88%).
[0189] Sample No. 2 exhibits a log P of 0.882, and such a favorable
log P value indicates that the compound has the capability of
passing the blood-brain barrier. The compound exhibits a Ki of 473
nM at .alpha.4.beta.2 receptor subtypes, indicating selectivity for
that receptor subtype. The binding constant indicates that the
compound exhibits high affinity binding to certain CNS nicotinic
receptors.
[0190] Sample No. 2 exhibits an E.sub.max value of 0% (at 100 uM)
for dopamine release. Sample No. 2 exhibits E.sub.max value of 0%
(at 1 00 M) at muscle-type receptors, indicating that the compound
does not induce activation of muscle-type receptors to any
significant degree. Sample No. 2 exhibits an E.sub.max value of 0%
(at 100 .mu.M) ganglionic-type receptors. The compound has the
capability to activate human CNS receptors without activating
muscle-type and ganglionic-type nicotinic acetylcholine receptors
to any significant degree. Thus, there is provided a therapeutic
window for utilization in the treatment of CNS disorders. That is,
at certain levels the compound shows CNS effects to a significant
degree but does not show undesirable muscle and ganglion effects to
any significant degree.
EXAMPLE 10
[0191] Sample No.3 is
2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane which was
prepared in accordance with the following techniques:
[0192] Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and
powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were
dissolved in methanol (25 ml) and stirred for 15 mins.
Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one
portion and the mixture was stirred for an additional 20 hrs. The
reaction mixture was then diluted with 40 ml water and cooled to
0.degree. C. yielding 2-((3-pyridyl)methylene)-1-a-
zabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was
collected, washed with distilled water and dried under vacuum (5.16
g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one
(3 g, 14.0 mmol) was dissolved in 200 ml methanol and sodium
borohydride (3 g, 79.6 mmol) was added in portions (exothermic
reaction) with vigorous stirring. After 1 hr of continued stirring,
acetone (100 ml) was slowly added to neutralize the remaining
borohydride reagent. The mixture was evaporated to dryness and the
resulting residue suspended in water (200 ml) and extracted three
times with 200 ml portions of chloroform. The chloroform phases
were combined, dried over MgSO.sub.4, and rotary evaporated to give
a clear oil; crystallization of the free base gave a quantitative
yield of 2-((3pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol as a
white precipitate.
2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-ol (1 g, 4.7
mmol) was combined with neat thionyl chloride (20 ml, 26.9 mmol)
stirred under a nitrogen atmosphere at 0.degree. C., the reaction
was than brought to room temperature and stirred for one additional
hour. Rotary evaporation at 60.degree. C. produced a viscous oil
which when suspended in ether afforded
3-chloro-2-((3-pyridyl)methylene)-1-azabicycl- o[2.2.2]octane
dihydrochloride as a hygroscopic precipitate (0.98 g, 91%). The
chloroquinuclidine (0.3 g, 1.3 mmol) was combined with 50 ml
ethanol in a hydrogenation vessel, then wet Raney nickel (2.5
grams) was added in one portion. Hydrogenation (50 psig) was
carried out for 6 hrs., after which time the slurry was carefully
filtered through a pad of Celite filter aid. Evaporation of solvent
gave the desired 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octane
dihydrochloride as a white reside which easily recrystallized from
ethanol-ether to give a white crystalline solid (0.21 g 70%).
[0193] Sample No. 3 exhibits a log P of 0.79, and such a favorable
log P value indicates that the compound has the capability of
passing the blood-brain barrier. The compound exhibits a Ki of 73
nM at .alpha.4.beta.2 receptor subtypes and a Ki of 35 nM at
.alpha.7 receptor subtypes. The low binding constant indicates that
the compound exhibits good high affinity binding to certain
relevant CNS nicotinic receptors.
[0194] Sample No. 3 exhibits an E.sub.max value of 0% (at 100 uM)
for dopamine release. Sample No. 3 exhibits EC.sub.50 of 2 uM and
an E.sub.max value of 100% at muscle-type receptors, indicating
that the compound does not induce activation of muscle-type
receptors to any significant degree. Sample No. 3 exhibits an
EC.sub.50 of 2 uM and an E.sub.max value of 115% at ganglionic-type
receptors. The compound has the capability to activate human CNS
receptors without activating muscle-type and ganglionic-type
nicotinic acetylcholine receptors to any significant degree. Thus,
there is provided a therapeutic window for utilization in the
treatment of CNS disorders. That is, at certain levels the compound
shows CNS effects to a significant degree but does not show
undesirable muscle and ganglion effects to any significant
degree.
EXAMPLE 11
[0195] 5 Sample No. 4 is
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-- ol, which was
prepared in accordance with the following techniques:
[0196] Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and
powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were
dissolved in methanol (25 ml) and stirred for 15 mins.
Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one
10 portion and the mixture was stirred for an additional 20 hrs.
The reaction mixture was then diluted with 40 ml water and cooled
to 0.degree. C. yielding
2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow
precipitate, which was collected, washed with distilled water and
dried under vacuum (5.16 g, 81.4%).
2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2- ]octan-3-one (1.0 g,
4.7 mmol) was combined with 50 ml methanol in a hydrogenation
vessel, then wet Raney nickel (5 grams) was added in one portion.
Hydrogenation (50 psig) was carried out for 12 hrs., after which
time the slurry was carefully filtered through a pad of Celite
filter aid. Evaporation of solvent gave
2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2- ]octan-3-ol as a light
yellow oil, which dissolved in ethanol/HCl give a white crystalline
solid upon cooling (0.78 g 77%).
[0197] Sample No. 4 exhibits a log P of 1.21, and such a favorable
log P value indicates that the compound has the capability of
passing the blood-brain barrier. The compound exhibits a Ki of 1.2
uM at .alpha.4.beta.2 receptor subtypes. The binding constant
indicates that the compound exhibits high affinity binding to
certain CNS nicotinic receptors.
[0198] Sample No. 4 exhibits an E.sub.max value of 0% (at 100 uM)
for dopamine release. Sample No. 4 exhibits E.sub.max value of 0%
(at 100 M) at muscle-type receptors, indicating that the compound
does not induce activation of muscle-type receptors to any
significant degree. Sample No. 4 exhibits an E.sub.max value of 29%
(at 100 uM) ganglionic-type receptors. The compound has the
capability to activate human CNS receptors without activating
muscle-type and ganglionic-type nicotinic acetylcholine receptors
to any significant degree. Thus, there is provided a therapeutic
window for utilization in the treatment of CNS disorders. That is,
at certain levels the compound shows CNS effects to a significant
degree but does not show undesirable muscle and ganglion effects to
any significant degree.
EXAMPLE NO. 12
[0199] Sample No. 5 is
2-((3-oxolanyl)methyl)-1-azabicyclo[2.2.2]octan-3-o- ne, which was
prepared in accordance with the following techniques:
[0200] Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and
powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were
dissolved in methanol (25 ml) and stirred for 15 mins.
Furan-3-carboxaldehyde (2.83 g, 29.5 mmol) was then added in one
portion and the mixture was stirred for an additional 20 hrs. The
reaction mixture was then diluted with 40 ml water and cooled to
0.degree. C. yielding 2-((3-furyl)methylene)-1-azabic-
yclo[2.2.2]octan-3-one as a yellow precipitate, which was
collected, washed with distilled water and dried under vacuum (5.16
g, 81.4%). 2-((3-Furyl)methylene)-1-azabicyclo[2.2.2]octan-3-one
(2.1 g, 10 mmol) was dissolved in methanol (100 ml) and 10%
palladium on charcoal (0.2 g) was carefully added under nitrogen.
The suspension was hydrogenated at 50 psig in a Parr hydrogenation
apparatus for 8 hrs followed by quenching of the catalyst with a
small amount of chloroform. The entire slurry was filtered through
a pad of Celite filter aid followed by additional washing of the
pad with methanol. Rotary evaporation of the pooled solvents gave
the desired product, 2-((3-oxolanyl)methyl)-1-azabicyclo[2.-
2.2]octan-3-one, as a clear oil that solidified upon cooling (2.05
g, 96.7%).
[0201] Sample No. 5 exhibits a log P of 1.05, and such a favorable
log P value indicates that the compound has the capability of
passing the blood-brain barrier. The compound exhibits a Ki of 5.5
uM at .alpha.4.beta.2 receptor subtypes. The binding constant
indicates that the compound exhibits high affinity binding to
certain CNS nicotinic receptors.
* * * * *