U.S. patent application number 10/865149 was filed with the patent office on 2004-11-11 for quinuclidine-substituted hetero-bicyclic aromatic compounds for the treatment of disease.
Invention is credited to Corbett, Jeffrey W., Groppi, Vincent E. JR., Piotrowski, David W., Rauckhorst, Mark R., Walker, Daniel Patrick, Wishka, Donn G..
Application Number | 20040224977 10/865149 |
Document ID | / |
Family ID | 27569622 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040224977 |
Kind Code |
A1 |
Walker, Daniel Patrick ; et
al. |
November 11, 2004 |
Quinuclidine-substituted hetero-bicyclic aromatic compounds for the
treatment of disease
Abstract
The invention provides compounds of Formula I: 1 wherein W.sup.0
is a bicyclic moiety and is 2 These compounds may be in the form of
pharmaceutical salts or compositions, may be in pure enantiomeric
form or racemic mixtures, and are useful to treat diseases or
conditions in which .alpha.7 is known to be involved.
Inventors: |
Walker, Daniel Patrick;
(Noank, CT) ; Wishka, Donn G.; (Mystic, CT)
; Corbett, Jeffrey W.; (Portage, MI) ; Rauckhorst,
Mark R.; (Portage, MI) ; Piotrowski, David W.;
(Groton Long Pointe, CT) ; Groppi, Vincent E. JR.;
(Kalamazoo, MI) |
Correspondence
Address: |
PHARMACIA & UPJOHN
301 HENRIETTA ST
0228-32-LAW
KALAMAZOO
MI
49007
US
|
Family ID: |
27569622 |
Appl. No.: |
10/865149 |
Filed: |
June 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10865149 |
Jun 10, 2004 |
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10163565 |
Jun 6, 2002 |
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60297629 |
Jun 12, 2001 |
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60297630 |
Jun 12, 2001 |
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60297631 |
Jun 12, 2001 |
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60297632 |
Jun 12, 2001 |
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60297633 |
Jun 12, 2001 |
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60328548 |
Oct 11, 2001 |
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60373496 |
Apr 18, 2002 |
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Current U.S.
Class: |
514/305 ;
546/135 |
Current CPC
Class: |
A61P 25/18 20180101;
A61P 25/24 20180101; A61P 25/30 20180101; C07D 453/02 20130101;
A61P 25/16 20180101; A61P 27/06 20180101; A61P 43/00 20180101; A61P
25/00 20180101; A61P 25/22 20180101; A61P 35/00 20180101; A61P
25/14 20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/305 ;
546/135 |
International
Class: |
C07D 453/04 |
Claims
1-98. (canceled)
99. A method for treating a disease or condition in a mammal in
need thereof, wherein the .alpha.7 nicotinic acetylcholine receptor
is implicated comprising administering to the mammal a
therapeutically effective amount of compound of Formula I:
42wherein W.sup.0 is a bicyclic moiety and is 43X is O, or S;
R.sub.1 is H, alkyl, cycloalkyl, halogenated alkyl, substituted
phenyl, or substituted naphthyl; R.sub.2 is H, alkyl, halogenated
alkyl, substituted alkyl, cycloalkyl, or aryl; R.sub.3 is H, F,
alkyl, halogenated alkyl, substituted alkyl, lactam
heterocycloalkyl, phenoxy, substituted phenoxy, R.sub.7, R.sub.9,
--N(R.sub.4)-aryl, --O-substituted phenyl, --O-substituted
naphthyl, --S-substituted phenyl, --S-substituted naphthyl, alkyl
substituted on the .omega. carbon with naphthyl, or alkyl
substituted on the .omega. carbon with substituted naphthyl; W is
C(H) where V--Z--Y is selected from O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5), O--C(R.sub.3)(R.sub.5)--O- ,
S--C(R.sub.3).dbd.N, S--C(R.sub.5)(R.sub.3)--N(R.sub.4),
S--N.dbd.C(R.sub.5), N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub.3)(R.sub.5)--C(R.sub.5).sub.2; Q is
N(R.sub.19), O, or S; W is N where V--Z--Y is selected from
O--C(R.sub.3).dbd.N, O--C(R.sub.5)(R.sub.3)--N(R.sub.4),
O--C(R.sub.5)(R.sub.3)--S, O--N.dbd.C(R.sub.5)
O--C(R.sub.3)(R.sub.5)--O, S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).dbd.C(R.sub.3)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub- .3)(R.sub.5)--C(R.sub.5).sub.2; R.sub.4
is H, or alkyl; R.sub.5 is H, F, Br, Cl, I, alkyl, substituted
alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl,
heterocycloalkyl, substituted heterocycloalkyl, lactam
heterocycloalkyl, --CN, --NO.sub.2, --OR.sub.1, --C(O)NH.sub.2,
--C(O)N(R.sub.16).sub.2, --NHR.sub.1, --NR.sub.1COR.sub.16,
--N(R.sub.10).sub.2, --SR.sub.1, --C(O)R.sub.16, --CO.sub.2R.sub.1,
aryl, R.sub.7, or R.sub.9; R.sub.6 is H, F, Cl, Br, I, --CN,
--CF.sub.3, --OR.sub.16, --SR.sub.16, or --N(R.sub.16).sub.2;
R.sub.7 is 5-membered heteroaromatic mono-cyclic moieties
containing within the ring 1-3 heteroatoms independently selected
from the group consisting of --O--, .dbd.N--, --N(R.sub.19)--, and
--S--, and having 0-1 substituent selected from R.sub.20 and
further having 0-3 substituents independently selected from F, Cl,
Br, or I, or R.sub.7 is 9-membered fused-ring moieties having a
6-membered ring fused to a 5-membered ring and having the formula
44wherein E is O, S, or NR.sub.19, 45wherein E and G are
independently selected from CR.sub.18, O, S, N, or NR.sub.19, and A
is CR.sub.18 or N, or 46wherein E and G are independently selected
from CR.sub.18, O, S, N, or NR.sub.19, and A is CR.sub.18 or N,
each 9-membered fused-ring moiety having 0-1 substituent selected
from R.sub.20 and further having 0-3 substituent(s) independently
selected from F, Cl, Br, or I, and having a bond directly or
indirectly attached to the core molecule where valency allows in
either the 6-membered or the 5-membered ring of the fused-ring
moiety; Each R.sub.8 is independently F, Br, Cl, I, alkyl,
substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl,
halogenated alkenyl, alkynyl, substituted alkynyl, halogenated
alkynyl, --CN, --CF.sub.3, --OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1,
--SR.sub.1, --CO.sub.2R.sub.1, aryl, phenoxy, substituted phenoxy,
heteroaryl, --N(R.sub.4)-aryl, or --O-substituted aryl. R.sub.9 is
6-membered heteroaromatic mono-cyclic moieties containing within
the ring 1-3 heteroatoms selected from .dbd.N-- and having 0-1
substituent selected from R.sub.20 and 0-3 substituent(s)
independently selected from F, Cl, Br, or I, or R.sub.9 is
10-membered heteroaromatic bi-cyclic moieties containing within one
or both rings 1-3 heteroatoms selected from .dbd.N--, including,
but not limited to, quinolinyl or isoquinolinyl, each 10-membered
fused-ring moiety having 0-1 substituent selected from R.sub.20 and
0-3 substituent(s) independently selected from F, Cl, Br, or I and
having a bond directly or indirectly attached to the core molecule
where valency allows; Each R.sub.10 is independently H, alkyl,
cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent
selected from R.sub.13, cycloalkyl substituted with 1 substituent
selected from R.sub.13, heterocycloalkyl substituted with 1
substituent selected from R.sub.13, halogenated alkyl, halogenated
cycloalkyl, halogenated heterocycloalkyl, phenyl, or substituted
phenyl; Each R.sub.11 is independently H, alkyl, cycloalkyl,
heterocyclo-alkyl, halogenated alkyl, halogenated cycloalkyl, or
halogenated heterocycloalkyl; R.sub.13 is --OR.sub.11, --SR.sub.11,
--NR.sub.11R.sub.11, --C(O)R.sub.11, --C(O)NR.sub.11R.sub.11, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2NR.sub.11R.sub.11,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2; R.sub.16 is H, alkyl,
substituted alkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl,
substituted heterocycloalkyl, substituted phenyl, or substituted
naphthyl; Each R.sub.18 is independently selected from H, F, Cl,
Br, I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,
halogenated cycloalkyl, halogenated heterocycloalkyl, substituted
alkyl, substituted cycloalkyl, substituted heterocycloalkyl,
--OR.sub.11, --SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11,
--NO.sub.2, --C(O)NR.sub.11R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, or --NR.sub.11S(O).sub.2R.sub.11, or
a bond directly or in-directly attached to the core molecule,
provided that there is only one said bond to the core molecule
within the 9-membered fused-ring moiety, further provided that the
fused-ring moiety has 0-1 substituent selected from alkyl,
cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated
cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,
substituted cycloalkyl, substituted heterocycloalkyl, --OR.sub.11,
--SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11, --NO.sub.2,
--C(O)NR.sub.11R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, or --NR.sub.11S(O).sub.2R.sub.11,
and further provided that the fused-ring moiety has 0-3
substituent(s) selected from F, Cl, Br, or I; R.sub.19 is H, alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, halogenated
cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 1
substituent selected from R.sub.20 and further having 0-3
substituents independently selected from F, Cl, Br, or I; R.sub.20
is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,
halogenated cycloalkyl, halogenated heterocycloalkyl, --OR,.sub.11,
--SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11,
--C(O)NR.sub.11R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, --NR.sub.11S(O).sub.2R,.sub.11,
--NO.sub.2, alkyl substituted with 1-4 substituent(s) independently
selected from F, Cl, Br, I, or R.sub.13, cycloalkyl substituted
with 1-4 substituent(s) independently selected from F, Cl, Br, I,
or R.sub.13, or heterocycloalkyl substituted with 1-4
substituent(s) independently selected from F, Cl, Br, I, or
R.sub.13; or pharmaceutically acceptable salt, or racemic mixture
thereof; wherein the disease or condition is psychosis, attention
deficit disorder, attention deficit hyperactivity disorder, mood
and affective disorders, amyotrophic lateral sclerosis, borderline
personality disorder, traumatic brain injury, behavioral and
cognitive problems associated with brain tumors, AIDS dementia
complex, dementia associated with Down's syndrome, dementia
associated with Lewy Bodies, Huntington's disease, depression,
general anxiety disorder, age-related macular degeneration,
Parkinson's disease, tardive dyskinesia, Pick's disease, post
traumatic stress disorder, dysregulation of food intake including
bulemia and anorexia nervosa, withdrawal symptoms associated with
smoking cessation and dependant drug cessation, Gilles de la
Tourette's Syndrome, glaucoma, neurodegeneration associated with
glaucoma, or symptoms associated with pain.
100. The method of claim 99, wherein X is O, and R.sub.1 is H.
101. The method of claim 100, wherein R.sub.2 is H, alkyl,
substituted alkyl, halogenated alkyl, or cycloalkyl.
102. The method of claim 101, wherein W.sup.0 includes
1,3-benzoxazol-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzothiazol-6-yl,
indan-5-yl, 1,3-benzodioxol-5-yl, [1,3]oxazolo[5,4-c]pyridin-6-yl,
2-benzoisothiophen-5-yl, 1,3-benzothiazol-5-yl
1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-5-yl, or 1H-indazol-6-yl,
optionally substituted with F, Br, Cl, alkyl, halogenated alkyl,
substituted alky, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl,
heterocycloalkyl, substituted heterocycloalkyl, lactam
heterocycloalkyl, phenoxy, substituted phenoxy, --CF.sub.3, --CN,
--NO.sub.2, --OR.sub.1, --NHR.sub.1, --N(R.sub.10).sub.2,
--N(R.sub.4)-aryl, --SR.sub.1, --C(O)N(R.sub.16).sub.2, or
--NR.sub.1COR.sub.16.
103. The method of claim 102, wherein the compound of Formula I has
the R stereochemistry at C3 of quinuclidine.
104. The method of claim 103, wherein the compound of Formula I
includes
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamid-
e;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamid-
e; N-((3R)1-azabicyclo
[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxami-
de;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-ca-
rboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carbox-
amide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzo-
xazole-6-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-
-benzoxazole-5-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-y-
l)-2-methyl-1,3-benzoxazole-5-carboxamide;
N-((2S,3R)-2-methyl-1-azabicycl-
o[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide; N-((2S
,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo
[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carb- oxamide; N-[(2S
,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-
-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl-
]-2-benzoisothiophene-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo
[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-a-
zabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazo-
le-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-inda-
zole-6-carboxamide; or a pharmaceutically acceptable salt
thereof.
105. The method of claim 103, wherein the compound of Formula I
includes
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-
I,2-benzisothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carbox-
amide; N-[(3R)-1-azabicyclo
[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-5- -carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisothi-
azole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-ben-
zisothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopr-
opyl-1,3-benzoxazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-
-cyclopropyl-1,3-benzoxazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-
-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-5-ca-
rboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-
-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-benzothi-
azole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benz-
othiazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3--
benzothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-
-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-et-
hyl-1,3-benzodioxole-5-carboxamide; N-[(3R)-1-azabicyclo
[2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2H-isoindole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[5,4-c]pyridine-6-carbox-
amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyridine-6--
carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]dioxolo[4,5-c]pyridi-
ne-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[4,5-c]p-
yridine-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-
-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl-
]-1H-indazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3--
yl]-1H-indazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct--
3-yl]-3-methyl-1H-indazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo-
[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-ca-
rboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-ind-
azole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]--1,2-
-benzisothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-
-3-yl]-1,2-benzisothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo-
[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiaz-
ole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-meth-
yl-1,2-benzisothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2-
.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzox-
azole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cy-
clopropyl-1,3-benzoxazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[-
2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzot-
hiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2--
methyl-1,3-benzothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2-
.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo
[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazo- le-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-
-1,3-benzothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]o-
ct-3-yl]-2-methyl-1,3-benzodioxole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-az-
abicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodi-
oxole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-be-
nzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-
H-isoindole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl-
]-1H-benzimidazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]o- ct-3-yl][1,3]thiazolo
[5,4-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyrid-
ine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]di-
oxolo[4,5-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2-
]oct-3-yl][1,3]oxazolo[4,5-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-c]pyridin-
e-6-carboxamide; or a pharmaceutically acceptable salt thereof.
106. The method of claim 102, wherein the compound of Formula I has
the S stereochemistry at C3 of quinuclidine.
107. The method of claim 106, wherein the compound of Formula I
includes
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide;
N-((3S)1-azabicyclo
[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxami- de;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide;
N-((3S)1-azabicyclo
[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxami- de;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide;
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxa-
mide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxami-
de;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxa-
mide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-ca-
rboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide; or
a pharmaceutically acceptable salt thereof.
108. The method of claim 99, wherein the disease or condition is
psychosis.
109. The method of claim 100, wherein the disease or condition is
psychosis.
110. The method of claim 101, wherein the disease or condition is
psychosis.
111. The method of claim 102, wherein the disease or condition is
psychosis.
112. The method of claim 103, wherein the disease or condition is
psychosis.
113. The method of claim 104, wherein the disease or condition is
psychosis.
114. The method of claim 105, wherein the disease or condition is
psychosis.
115. The method of claim 106, wherein the disease or condition is
psychosis.
116. The method of claim 107, wherein the disease or condition is
psychosis.
117. The method of claim 99, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain
118. The method of claim 100, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
119. The method of claim 101, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
120. The method of claim 102, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
121. The method of claim 103, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
122. The method of claim 104, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
123. The method of claim 105, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
124. The method of claim 106, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
125. The method of claim 107, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, mood and affective disorders, amyotrophic lateral
sclerosis, borderline personality disorder, traumatic brain injury,
behavioral and cognitive problems associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
depression, general anxiety disorder, age-related macular
degeneration, Parkinson's disease, tardive dyskinesia, Pick's
disease, post traumatic stress disorder, dysregulation of food
intake including bulemia and anorexia nervosa, withdrawal symptoms
associated with smoking cessation and dependant drug cessation,
Gilles de la Tourette's Syndrome, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Serial No. 60/297629 filed on 12 Jun. 2001, under 35
USC 119(e)(i); U.S. provisional application Serial No. 60/297630
filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional
application Serial No. 60/297631 filed on 12 Jun. 2001, under 35
USC 119(e)(i); U.S. provisional application Serial No. 60/297632
filed on 12 Jun. 2001, under 35 USC 119(e)(i); U.S. provisional
application Serial No. 60/297633 filed on 12 Jun. 2001, under 35
USC 119(e)(i); U.S. provisional application Serial No. 60/328548
filed on 11 Oct. 2001, under 35 USC 119(e)(i); and U.S. provisional
application Serial No. 60/373496 filed on 18 April 2002, under 35
USC 119(e)(i), which are incorporated herein by reference in their
entirety.
FIELD OF INVENTION
[0002] Nicotinic acetylcholine receptors (nAChRs) play a large role
in central nervous system (CNS) activity. Particularly, they are
known to be involved in cognition, learning, mood, emotion, and
neuroprotection. There are several types of nicotinic acetylcholine
receptors, and each one appears to have a different role in
regulating CNS function. Nicotine affects all such receptors, and
has a variety of activities. Unfortunately, not all of the
activities are desirable. In fact, one of the least desirable
properties of nicotine is its addictive nature and the low ratio
between efficacy and safety. The present invention relates to
molecules that have a greater effect upon the .alpha.7 nAChRs as
compared to other closely related members of this large
ligand-gated receptor family. Thus, the invention provides
compounds that are active drug molecules with fewer side
effects.
BACKGROUND OF THE INVENTION
[0003] Cell surface receptors are, in general, excellent and
validated drug targets. nAChRs comprise a large family of
ligand-gated ion channels that control neuronal activity and brain
function. These receptors have a pentameric structure. In mammals,
this gene family is composed of nine alpha and four beta subunits
that co-assemble to form multiple subtypes of receptors that have a
distinctive pharmacology. Acetylcholine is the endogenous regulator
of all of the subtypes, while nicotine non-selectively activates
all nAChRs.
[0004] The .alpha.7 nAChR is one receptor system that has proved to
be a difficult target for testing. Native (.alpha.7 nAChR is not
routinely able to be stably expressed in most mammalian cell lines
(Cooper and Millar, Nature, 366(6454), p. 360-4, 1997). Another
feature that makes functional assays of .alpha.7 nAChR challenging
is that the receptor is rapidly (100 milliseconds) inactivated.
This rapid inactivation greatly limits the functional assays that
can be used to measure channel activity.
[0005] Recently, Eisele et al. has indicated that a chimeric
receptor formed between the N-terminal ligand binding domain of the
.alpha.7 nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993),
and the pore forming C-terminal domain of the 5-HT.sub.3 receptor
expressed well in Xenopus oocytes while retaining nicotinic agonist
sensitivity. Eisele et al. used the N-terminus of the avian (chick)
form of the .alpha.7 nAChR receptor and the C-terminus of the mouse
form of the 5-HT.sub.3 gene. However, under physiological
conditions the .alpha.7 nAChR is a calcium channel while the
5-HT.sub.3R is a sodium and potassium channel. Indeed, Eisele et
al. teaches that the chicken .alpha.7 nAChR/ mouse 5-HT.sub.3R
behaves quite differently than the native .alpha.7 nAChR with the
pore element not conducting calcium but actually being blocked by
calcium ions. WO 00/73431 A2 reports on assay conditions under
which the 5-HT.sub.3R can be made to conduct calcium. This assay
may be used to screen for agonist activity at this receptor.
[0006] WO 00/73431 A2 discloses two binding assays to directly
measure the affinity and selectivity of compounds at the .alpha.7
nAChR and the 5-HT.sub.3R. The combined use of these functional and
binding assays may be used to identify compounds that are selective
agonists of the .alpha.7 nAChR.
SUMMARY OF THE INVENTION
[0007] The present invention discloses compounds of the Formula I:
3
[0008] wherein W.sup.0 is a bicyclic moiety and is 4
[0009] X is O, or S;
[0010] R.sub.1 is H, alkyl, cycloalkyl, halogenated alkyl,
substituted phenyl, or substituted naphthyl;
[0011] R.sub.2 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, or aryl;
[0012] R.sub.3 is H, F, alkyl, halogenated alkyl, substituted
alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy,
R.sub.7, R.sub.9, --N(R.sub.4)-aryl, --N(R.sub.4)-substituted
phenyl, --N(R.sub.4)-substituted naphthyl, --O-substituted phenyl,
--O-substituted naphthyl, --S-substituted phenyl, --S-substituted
naphthyl, or alkyl substituted on the w carbon with R.sub.15 where
said .omega. carbon is determined by counting the longest carbon
chain of the alkyl moiety with the C-1 carbon being the carbon
attached to the bicyclic moiety W.sup.0 and the .omega. carbon
being the carbon furthest, e.g., separated by the greatest number
of carbon atoms in the chain, from said C-1 carbon;
[0013] W is C(H) where
[0014] V--Z--Y is selected from O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5), O--C(R.sub.3)(R.sub.8)--O,
O--C(R.sub.3)(R.sub.5)--O- , S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2,
C(R.sub.5)(R.sub.17)--C(R.sub.3)(R.sub.17)--C(R.sub.5)(R.sub.17),
or C(R.sub.5).sub.2--C(R.sub.3)(R.sub.5)--C(R.sub.5).sub.2;
[0015] Q is N(R.sub.19), O, or S;
[0016] W is N where
[0017] V--Z--Y is selected from O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5) O--C(R.sub.3)(R.sub.5)--O, S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.- sub.4),
C(R.sub.5).sub.2--O--N(R.sub.4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).dbd.C(R.sub.3)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub- .3)(R.sub.5)--C(R.sub.5).sub.2;
[0018] W.sup.1, W.sup.2, W.sup.3, W.sup.4 are each independently N
or C(R.sub.21), provided that no more than two of W.sup.1, W.sup.2,
W.sup.3, W.sup.4 are N, and further provided when more than two of
W.sup.1, W.sup.2, W.sup.3, W.sup.4 are C(R.sub.21) that no more
than two R.sub.21 are other than H;
[0019] J is N(R.sub.23), S, or O;
[0020] R.sub.4 is H, or alkyl;
[0021] R.sub.5 is H, F, Br, Cl, I, alkyl, substituted alkyl,
halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl,
heterocycloalkyl, substituted heterocycloalkyl, lactam
heterocycloalkyl, --CN, --NO.sub.2, --OR.sub.1,
--C(O)N(R.sub.16).sub.2, --NHR.sub.1, --NR.sub.1COR.sub.16,
--N(R.sub.10).sub.2, --SR.sub.1, --C(O)R.sub.16, --CO.sub.2R.sub.1,
aryl, R.sub.7, or R.sub.9;
[0022] R.sub.6 is H, F, Cl, Br, I, --CN, --CF.sub.3, --OR.sub.16,
--SR.sub.16, or --N(R.sub.16).sub.2;
[0023] R.sub.7 is 5-membered heteroaromatic mono-cyclic moieties
containing within the ring 1-3 heteroatoms independently selected
from the group consisting of --O--, .dbd.N--, --N(R.sub.19)--, and
--S--, and having 0-1 substituent selected from R.sub.20 and
further having 0-3 substituents independently selected from F, Cl,
Br, or I, or R.sub.7 is 9-membered fused-ring moieties having a
6-membered ring fused to a 5-membered ring and having the formula
5
[0024] wherein E is O, S, or NR.sub.19, 6
[0025] wherein E and G are independently selected from CR.sub.18,
O, S, N, or NR.sub.19, and A is CR.sub.18 or N, or 7
[0026] wherein E and G are independently selected from CR.sub.18,
O, S, N, or NR.sub.19, and A is CR.sub.18 or N, each 9-membered
fused-ring moiety having 0-1 substituent selected from R.sub.20 and
further having 0-3 substituent(s) independently selected from F,
Cl, Br, or I, and having a bond directly or indirectly attached to
the core molecule where valency allows in either the 6-membered or
the 5-membered ring of the fused-ring moiety;
[0027] Each R.sub.8 is independently F, Br, Cl, I, alkyl,
substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl,
halogenated alkenyl, alkynyl, substituted alkynyl, halogenated
alkynyl, --CN, --CF.sub.3, --OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1,
--SR.sub.1, --CO.sub.2R.sub.1, aryl, phenoxy, substituted phenoxy,
heteroaryl, --N(R.sub.4)-aryl, or --O-substituted aryl.
[0028] R.sub.9 is 6-membered heteroaromatic mono-cyclic moieties
containing within the ring 1-3 heteroatoms selected from .dbd.N-
and having 0-1 substituent selected from R.sub.20 and 0-3
substituent(s) independently selected from F, Cl, Br, or I, or
R.sub.9 is 10-membered heteroaromatic bi-cyclic moieties containing
within one or both rings 1-3 heteroatoms selected from .dbd.N--,
including, but not limited to, quinolinyl or isoquinolinyl, each
10-membered fused-ring moiety having 0-1 substituent selected from
R.sub.20 and 0-3 substituent(s) independently selected from F, Cl,
Br, or I and having a bond directly or indirectly attached to the
core molecule where valency allows;
[0029] Each R.sub.10 is independently H, alkyl, cycloalkyl,
heterocycloalkyl, alkyl substituted with 1 substituent selected
from R.sub.13, cycloalkyl substituted with 1 substituent selected
from R.sub.13, heterocycloalkyl substituted with 1 substituent
selected from R.sub.13, halogenated alkyl, halogenated cycloalkyl,
halogenated heterocycloalkyl, phenyl, or substituted phenyl;
[0030] Each R.sub.11 is independently H, alkyl, cycloalkyl,
heterocyclo-alkyl, halogenated alkyl, halogenated cycloalkyl, or
halogenated heterocycloalkyl;
[0031] R.sub.13 is --OR.sub.11, --SR.sub.11, --NR.sub.11R.sub.11,
--C(O)R.sub.11, --C(O)NR.sub.11R.sub.11, --CN, --CF.sub.3,
--NR.sub.11,C(O)R.sub.11, --S(O).sub.2NR.sub.11R.sub.11,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2;
[0032] R.sub.15 is aryl, R.sub.7, or R.sub.9;
[0033] R.sub.16 is H, alkyl, substituted alkyl, cycloalkyl,
halogenated alkyl, heterocycloalkyl, substituted heterocycloalkyl,
substituted phenyl, or substituted naphthyl;
[0034] One of R.sub.17 is H, alkyl, substituted alkyl, halogenated
alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,
substituted alkynyl, halogenated alkynyl, --CN, F, Br, Cl, I,
--OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1, --SR.sub.1,
--CO.sub.2R.sub.1, aryl, R.sub.7, or R.sub.9, and each of the other
two R.sub.17 is independently selected from alkyl, substituted
alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, --CN,
F, Br, Cl, I, --OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1, --SR.sub.1,
--CO.sub.2R.sub.1, aryl, R.sub.7, or R.sub.9;
[0035] Each R.sub.18 is independently selected from H, F, Cl, Br,
I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,
halogenated cycloalkyl, halogenated heterocycloalkyl, substituted
alkyl, substituted cycloalkyl, substituted heterocycloalkyl,
--OR.sub.11, --SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11,
--NO.sub.2, --C(O)NR.sub.11R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, or --NR.sub.11S(O).sub.2R.sub.11, or
a bond directly or indirectly attached to the core molecule,
provided that there is only one said bond to the core molecule
within the 9-membered fused-ring moiety, further provided that the
fused-ring moiety has 0-1 substituent selected from alkyl,
cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated
cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,
substituted cycloalkyl, substituted heterocycloalkyl, --OR.sub.11,
--SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11, --NO.sub.2,
--C(O)NR.sub.11R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, or --NR.sub.11S(O).sub.2R.sub.11,
and further provided that the fused-ring moiety has 0-3
substituent(s) selected from F, Cl, Br, or I;
[0036] R.sub.19 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl,
or phenyl having 1 substituent selected from R.sub.20 and further
having 0-3 substituents independently selected from F, Cl, Br, or
I;
[0037] R.sub.20 is alkyl, cycloalkyl, heterocycloalkyl, halogenated
alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,
--OR.sub.11, --SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11,
--C(O)NR.sub.11R.sub.11- , --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, --NR.sub.11S(O).sub.2R,.sub.11,
--NO.sub.2, alkyl substituted with 1-4 substituent(s) independently
selected from F, Cl, Br, I, or R.sub.13, cycloalkyl substituted
with 1-4 substituent(s) independently selected from F, Cl, Br, I,
or R.sub.13, or heterocycloalkyl substituted with 1-4
substituent(s) independently selected from F, Cl, Br, I, or
R.sub.13;
[0038] R.sub.21 is H, F, Cl, Br, I, alkyl, substituted alkyl,
halogenated alkyl, cycloalkyl, --CN, --NR.sub.22R.sub.22,
--OR.sub.22, or --SR.sub.22;
[0039] Each R.sub.22 is independently H, alkyl, substituted alkyl,
cycloalkyl, halogenated alkyl, substituted cycloalkyl,
heterocycloalkyl, or substituted heterocycloalkyl;
[0040] R.sub.23 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, halogenated heterocycloalkyl, substituted
heterocycloalkyl, substituted phenyl, naphthyl, substituted
naphthyl, R.sub.7, or R.sub.9;
[0041] or pharmaceutical composition, pharmaceutically acceptable
salt, racemic mixture, or pure enantiomer thereof.
[0042] The compounds of Formula I are use to treat any one of or
combination of cognitive and attention deficit symptoms of
Alzheimer's, neurodegeneration associated with diseases such as
Alzheimer's disease, pre-senile dementia (mild cognitive
impairment), senile dementia, schizophrenia, psychosis, attention
deficit disorder, attention deficit hyperactivity disorder, mood
and affective disorders, amyotrophic lateral sclerosis, borderline
personality disorder, traumatic brain injury, behavioral and
cognitive problems associated with brain tumors, AIDS dementia
complex, dementia associated with Down's syndrome, dementia
associated with Lewy Bodies, Huntington's disease, depression,
general anxiety disorder, age-related macular degeneration,
Parkinson's disease, tardive dyskinesia, Pick's disease, post
traumatic stress disorder, dysregulation of food intake including
bulemia and anorexia nervosa, withdrawal symptoms associated with
smoking cessation and dependant drug cessation, Gilles de la
Tourette's Syndrome, glaucoma, neurodegeneration associated with
glaucoma, or symptoms associated with pain.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Surprisingly, we have found that compounds of Formula I:
8
[0044] wherein W.sup.0 is a bicyclic moiety and is 9
[0045] R.sub.1 is H, alkyl, cycloalkyl, halogenated alkyl,
substituted phenyl, or substituted naphthyl;
[0046] Alkyl is both straight- and branched-chain moieties having
from 1-6 carbon atoms, unless otherwise specified;
[0047] Halogenated alkyl is an alkyl moiety having from 1-6 carbon
atoms and having 1 to (2n+1) substituent(s) independently selected
from F, Cl, Br, or I where n is the maximum number of carbon atoms
in the moiety;
[0048] Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon
atoms;
[0049] Substituted phenyl is a phenyl either having 1-4
substituents independently selected from F, Cl, Br, or I, or having
1 substituent selected from R.sub.12 and 0-3 substituents
independently selected from F, Cl, Br, or I;
[0050] Substituted naphthyl is a naphthalene moiety either having
1-4 substituents independently selected from F, Cl, Br, or I, or
having 1 substituent selected from R.sub.12 and 0-3 substituents
independently selected from F, Cl, Br, or I, where the substitution
can be independently on either only one ring or both rings of said
naphthalene moiety;
[0051] R.sub.2 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, or aryl;
[0052] Aryl is phenyl, substituted phenyl, naphthyl, or substituted
naphthyl;
[0053] Substituted alkyl is an alkyl moiety from 1-6 carbon atoms
and having 0-3 substituents independently selected from F, Cl, Br,
or I and further having I substituent selected from --OR.sub.10,
--SR.sub.10, --NR.sub.10R.sub.10, --C(O)R.sub.10,
--C(O)NR.sub.10R.sub.10, --CN, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2NR.sub.10R.sub.10, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, R.sub.7, R.sub.9, phenyl, or substituted phenyl;
[0054] R.sub.3 is H, F, alkyl, halogenated alkyl, substituted
alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy,
R.sub.7, R.sub.9, --N(R.sub.4)-aryl, --O-substituted phenyl,
--O-substituted naphthyl, --S-substituted phenyl, --S-substituted
naphthyl, or alkyl substituted on the .omega. carbon with R.sub.15
where said .omega. carbon is determined by counting the longest
carbon chain of the alkyl moiety with the C-1 carbon being the
carbon attached to the bicyclic moiety W.sup.0 and the .omega.
carbon being the carbon furthest, e.g., separated by the greatest
number of carbon atoms in the chain, from said C-1 carbon;
[0055] Lactam heterocycloalkyl is a cyclic moiety having from 4-7
atoms with one atom being only nitrogen with the bond to the lactam
heterocycloalkyl thru said atom being only nitrogen and having a
.dbd.O on a carbon adjacent to said nitrogen, and having up to 1
additional ring atom being oxygen, sulfur, or nitrogen and further
having 0-2 substituents selected from F, Cl, Br, I, or R.sub.14
where valency allows;
[0056] Substituted phenoxy is a phenoxy either having 1-3
substituents independently selected from F, Cl, Br, or I, or having
1 substituent selected from R.sub.12 and 0-2 substituents
independently selected from F, Cl, Br, or I;
[0057] W is C(H) where
[0058] V--Z--Y is selected from O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5), O--C(R.sub.3)(R.sub.8)--O,
O--C(R.sub.3)(R.sub.5)--O- , S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2,
C(R.sub.5)(R.sub.17)--C(R.sub.3)(R.sub.17)--C(R.sub.5)(R.sub.17),
or C(R.sub.5).sub.2--C(R.sub.3)(R.sub.5)--C(R.sub.5).sub.2;
[0059] Q is N(R.sub.19), O, or S;
[0060] W is N where
[0061] V--Z--Y is selected from O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5) O--C(R.sub.3)(R.sub.5)--O, S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.- sub.4),
C(R.sub.5).sub.2--O--N(R.sub.4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).dbd.C(R.sub.3)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub- .3)(R.sub.5)--C(R.sub.5).sub.2;
[0062] W.sup.1, W.sup.2, W.sup.3, W.sup.4 are each independently N
or C(R.sub.21), provided that no more than two of W.sup.1, W.sup.2,
W.sup.3, W.sup.4 are N, and further provided when more than two of
W.sup.1, W.sup.2, W.sup.3, W.sup.4 are C(R.sub.21) that no more
than two R.sub.21 are other than H;
[0063] J is N(R.sub.23), S, or O;
[0064] R.sub.4 is H, or alkyl;
[0065] R.sub.5 is H, F, Br, Cl, I, alkyl, substituted alkyl,
halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl,
heterocycloalkyl, substituted heterocycloalkyl, lactam
heterocycloalkyl, --CN, --NO.sub.2, --OR.sub.1,
--C(O)N(R.sub.16).sub.2, --NHR.sub.1, --NR.sub.1COR.sub.16,
--N(R.sub.10).sub.2, --SR.sub.1, --C(O)R.sub.16, --CO.sub.2R.sub.1,
aryl, R.sub.7, or R.sub.9;
[0066] Alkenyl is straight- and branched-chain moieties having from
2-6 carbon atoms and having at least one carbon-carbon double
bond;
[0067] Halogenated alkenyl is an unsaturated alkenyl moiety having
from 2-6 carbon atoms and having 1 to (2n-1) substituent(s)
independently selected from F, Cl, Br, or I where n is the maximum
number of carbon atoms in the moiety;
[0068] Substituted alkenyl is an unsaturated alkenyl moiety having
from 2-6 carbon atoms and having 0-3 substituents independently
selected from F, or Cl, and further having 1 substituent selected
from --OR.sub.10, --SR.sub.10, --NR.sub.10R.sub.10, --C(O)R.sub.10,
--C(O)NR.sub.10R.sub.10- , --NR.sub.10C(O)R.sub.10,
--S(O).sub.2NR.sub.10R.sub.10, --NR.sub.10S(O).sub.2R.sub.10, --CN,
R.sub.7, R.sub.9, phenyl, or substituted phenyl;
[0069] Alkynyl is straight- and branched-chained moieties having
from 2-6 carbon atoms and having at least one carbon-carbon triple
bond;
[0070] Halogenated alkynyl is an unsaturated alkynyl moiety having
from 3-6 carbon atoms and having 1 to (2n-3) substituent(s)
independently selected from F, Cl, Br, or I where n is the maximum
number of carbon atoms in the moiety;
[0071] Substituted alkynyl is an unsaturated alkynyl moiety having
from 3-6 carbon atoms and having 0-3 substituents independently
selected from F, or Cl, and further having 1 substituent selected
from --OR.sub.10, --SR.sub.10, --NR.sub.10R.sub.10, --C(O)R.sub.10,
--C(O)NR.sub.10R.sub.10- , --NR.sub.10C(O)R.sub.10,
--S(O).sub.2NR.sub.10R.sub.10, --NR.sub.10S(O).sub.2R.sub.10, --CN,
R.sub.7, R.sub.9, phenyl, or substituted phenyl;
[0072] Halogenated cycloalkyl is a cyclic moiety having from 3-6
carbon atoms and having 1-4 substituents independently selected
from F, or Cl;
[0073] Substituted cycloalkyl is a cyclic moiety having from 3-6
carbon atoms and having 0-3 substituents independently selected
from F, or Cl, and further having 1 substituent selected from
--OR.sub.10, --SR.sub.10, --NR.sub.10R.sub.10, --C(O)R.sub.10,
--CN, --C(O)NR.sub.10R.sub.10, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2NR.sub.10R.sub.10, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, or substituted phenyl;
[0074] Heterocycloalkyl is a cyclic moiety having 4-7 atoms with
1-2 atoms within the ring being --S--, --N(R.sub.19)--, or
--O--;
[0075] Halogenated heterocycloalkyl is a cyclic moiety having from
4-7 atoms with 1-2 atoms within the ring being --S--,
--N(R.sub.19)--, or --O--, and having 1-4 substituents
independently selected from F, or Cl;
[0076] Substituted heterocycloalkyl is a cyclic moiety having from
4-7 atoms with 1-2 atoms within the ring being --S--,
--N(R.sub.19)--, or --O- and having 0-3 substituents independently
selected from F, or Cl, and further having 1 substituent selected
from R.sub.7, R.sub.9, --OR.sub.10, --SR.sub.10,
--NR.sub.10R.sub.10, --C(O)R.sub.10, --C(O)NR.sub.10R.sub.10, --CN,
--NR.sub.10C(O)R.sub.10, --NO.sub.2, --S(O).sub.2NR.sub.10R.sub.10,
--NR.sub.10S(O).sub.2R.sub.10, phenyl, or phenyl having 1
substituent selected from R.sub.20 and further having 0-3
substituents independently selected from F, Cl, Br, or I;
[0077] R.sub.6 is H, F, Cl, Br, I, --CN, --CF.sub.3, --OR.sub.16,
--SR.sub.16, or --N(R.sub.16).sub.2;
[0078] R.sub.7 is 5-membered heteroaromatic mono-cyclic moieties
containing within the ring 1-3 heteroatoms independently selected
from the group consisting of --O--, .dbd.N--, --N(R.sub.19)--, and
--S--, and having 0-1 substituent selected from R.sub.20 and
further having 0-3 substituents independently selected from F, Cl,
Br, or I, or R.sub.7 is 9-membered fused-ring moieties having a
6-membered ring fused to a 5-membered ring and having the formula
10
[0079] wherein E is O, S, or NR.sub.19, 11
[0080] wherein E and G are independently selected from CR.sub.18,
O, S, N, or NR.sub.19, and A is CR.sub.18 or N, or 12
[0081] wherein E and G are independently selected from CR.sub.18,
O, S, N, or NR.sub.19, and A is CR.sub.18 or N, each 9-membered
fused-ring moiety having 0-1 substituent selected from R.sub.20 and
further having 0-3 substituent(s) independently selected from F,
Cl, Br, or I, and having a bond directly or indirectly attached to
the core molecule where valency allows in either the 6-membered or
the 5-membered ring of the fused-ring moiety;
[0082] Each R.sub.8 is independently F, Br, Cl, I, alkyl,
substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl,
halogenated alkenyl, alkynyl, substituted alkynyl, halogenated
alkynyl, --CN, --CF.sub.3, --OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1,
--SR.sub.1, --CO.sub.2R.sub.1, aryl, phenoxy, substituted phenoxy,
heteroaryl, --N(R.sub.4)-aryl, or --O-substituted aryl.
[0083] R.sub.9 is 6-membered heteroaromatic mono-cyclic moieties
containing within the ring 1-3 heteroatoms selected from .dbd.N--
and having 0-1 substituent selected from R.sub.20 and 0-3
substituent(s) independently selected from F, Cl, Br, or I, or
R.sub.9 is 10-membered heteroaromatic bi-cyclic moieties containing
within one or both rings 1-3 heteroatoms selected from .dbd.N--,
including, but not limited to, quinolinyl or isoquinolinyl, each
10-membered fused-ring moiety having 0-1 substituent selected from
R.sub.20 and 0-3 substituent(s) independently selected from F, Cl,
Br, or I and having a bond directly or indirectly attached to the
core molecule where valency allows;
[0084] Each R.sub.10 is independently H, alkyl, cycloalkyl,
heterocycloalkyl, alkyl substituted with 1 substituent selected
from R.sub.13, cycloalkyl substituted with 1 substituent selected
from R.sub.13, heterocycloalkyl substituted with 1 substituent
selected from R.sub.13, halogenated alkyl, halogenated cycloalkyl,
halogenated heterocycloalkyl, phenyl, or substituted phenyl;
[0085] Each R.sub.11 is independently H, alkyl, cycloalkyl,
heterocyclo-alkyl, halogenated alkyl, halogenated cycloalkyl, or
halogenated heterocycloalkyl;
[0086] R.sub.12 is --OR.sub.11, --SR.sub.11, alkyl, cycloalkyl,
heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,
halogenated heterocycloalkyl, substituted alkyl, substituted
cycloalkyl, substituted heterocycloalkyl, --NR.sub.11R.sub.11,
--C(O)R.sub.11, --NO.sub.2, --C(O)NR.sub.11R.sub.11, --CN,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2NR.sub.11R.sub.11, or
--NR.sub.11S(O).sub.2R.sub.11;
[0087] R.sub.13 is --OR,.sub.11, --SR.sub.11, --NR, R.sub.11,
--C(O)R.sub.11, --C(O)NR, R.sub.11, --CN, --CF.sub.3,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2NR.sub.11R.sub.11,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2;
[0088] R.sub.14 is alkyl, substituted alkyl, halogenated alkyl,
--OR.sub.11, --CN, --NO.sub.2, --NR.sub.10R.sub.10;
[0089] R.sub.15 is aryl, R.sub.7, or R.sub.9;
[0090] R.sub.16 is H, alkyl, substituted alkyl, cycloalkyl,
halogenated alkyl, heterocycloalkyl, substituted heterocycloalkyl,
substituted phenyl, or substituted naphthyl;
[0091] One of R.sub.17 is H, alkyl, substituted alkyl, halogenated
alkyl, alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,
substituted alkynyl, halogenated alkynyl, --CN, F, Br, Cl, I,
--OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1, --SR.sub.1,
--CO.sub.2R.sub.1, aryl, R.sub.7, or R.sub.9, and each of the other
two R.sub.17 is independently selected from alkyl, substituted
alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, --CN,
F, Br, Cl, I, --OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1, --SR.sub.1,
--CO.sub.2R.sub.1, aryl, R.sub.7, or R.sub.9;
[0092] Each R.sub.18 is independently selected from H, F, Cl, Br,
I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,
halogenated cycloalkyl, halogenated heterocycloalkyl, substituted
alkyl, substituted cycloalkyl, substituted heterocycloalkyl,
--OR.sub.11, --SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11,
--NO.sub.2, --C(O)NR, R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, or --NR.sub.11S(O).sub.2R.sub.11, or
a bond directly or indirectly attached to the core molecule,
provided that there is only one said bond to the core molecule
within the 9-membered fused-ring moiety, further provided that the
fused-ring moiety has 0-1 substituent selected from alkyl,
cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated
cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,
substituted cycloalkyl, substituted heterocycloalkyl, --OR.sub.11,
--SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11, --NO.sub.2,
--C(O)NR.sub.11R.sub.11, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, or --NR.sub.11S(O).sub.2R.sub.11,
and further provided that the fused-ring moiety has 0-3
substituent(s) selected from F, Cl, Br, or I;
[0093] R.sub.19 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl,
or phenyl having 1 substituent selected from R.sub.20 and further
having 0-3 substituents independently selected from F, Cl, Br, or
I;
[0094] R.sub.20 is alkyl, cycloalkyl, heterocycloalkyl, halogenated
alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,
--OR.sub.11, --SR.sub.11, --NR.sub.11R.sub.11, --C(O)R.sub.11,
--C(O)NR.sub.11R.sub.11- , --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2NR.sub.11R.sub.11, --NR.sub.11S(O).sub.2R,I,
--NO.sub.2, alkyl substituted with 1-4 substituent(s) independently
selected from F, Cl, Br, I, or R.sub.13, cycloalkyl substituted
with 1-4 substituent(s) independently selected from F, Cl, Br, I,
or R.sub.13, or heterocycloalkyl substituted with 1-4
substituent(s) independently selected from F, Cl, Br, I, or
R.sub.13;
[0095] R.sub.21 is H, F, Cl, Br, I, alkyl, substituted alkyl,
halogenated alkyl, cycloalkyl, --CN, --NR.sub.22R.sub.22,
--OR.sub.22, or --SR.sub.22;
[0096] Each R.sub.22 is independently H, alkyl, substituted alkyl,
cycloalkyl, halogenated alkyl, substituted cycloalkyl,
heterocycloalkyl, or substituted heterocycloalkyl;
[0097] R.sub.23 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, halogenated heterocycloalkyl, substituted
heterocycloalkyl, substituted phenyl, naphthyl, substituted
naphthyl, R.sub.7, or R.sub.9;
[0098] or pharmaceutical composition, pharmaceutically acceptable
salt, racemic mixture, or pure enantiomer thereof useful to treat
any one of or combination of cognitive and attention deficit
symptoms of Alzheimer's, neurodegeneration associated with diseases
such as Alzheimer's disease, pre-senile dementia (mild cognitive
impairment), senile dementia, schizophrenia, psychosis, attention
deficit disorder, attention deficit hyperactivity disorder, mood
and affective disorders, amyotrophic lateral sclerosis, borderline
personality disorder, traumatic brain injury, behavioral and
cognitive problems associated with brain tumors, AIDS dementia
complex, dementia associated with Down's syndrome, dementia
associated with Lewy Bodies, Huntington's disease, depression,
general anxiety disorder, age-related macular degeneration,
Parkinson's disease, tardive dyskinesia, Pick's disease, post
traumatic stress disorder, dysregulation of food intake including
bulemia and anorexia nervosa, withdrawal symptoms associated with
smoking cessation and dependant drug cessation, Gilles de la
Tourette's Syndrome, glaucoma, neurodegeneration associated with
glaucoma, or symptoms associated with pain.
[0099] In another aspect, the invention includes methods of
treating a mammal suffering from schizophrenia or psychosis by
administering compounds of Formula I in conjunction with
antipsychotic drugs. The compounds of Formula I and the
antipsychotic drugs can be administered simultaneously or at
separate intervals. When administered simultaneously the compounds
of Formula I and the antipsychotic drugs can be incorporated into a
single pharmaceutical composition. Alternatively, two separate
compositions, i.e., one containing compounds of Formula I and the
other containing antipsychotic drugs, can be administered
simultaneously.
[0100] The present invention also includes the intermediates, the
processes to make them and the compounds of the present invention,
pharmaceutical compositions containing the active compounds, and
methods to treat the identified diseases.
[0101] One group of compounds of Formula I includes compounds
having the R configuration at the C3 position of the quinuclidine
ring. Another group of compounds of Formula I includes compounds
having the S configuration at the C3 position of the quinuclidine
ring. Another group of compounds of Formula I includes compounds
wherein the quinuclidine has S configuration at C2 when R.sub.2 is
other than H and at C2. Another group of compounds of Formula I
includes compounds wherein the quinuclidine has 2S,3R configuration
at C2 when R.sub.2 is other than H at C2 with the amide-type bond
being at C3.
[0102] Another group of compounds of Formula I includes compounds
wherein X is O. Another group of compounds of Formula I includes
compounds where R.sub.1 is H. Another group of compounds of Formula
I includes compounds wherein R.sub.2 is H. Another group of
compounds of Formula I includes compounds wherein R.sub.1 is alkyl,
cycloalkyl, halogenated alkyl, substituted phenyl, or substituted
naphthyl. Another group of compounds of Formula I includes
compounds wherein R.sub.2 is alkyl. Another group of compounds of
Formula I includes compounds wherein R.sub.2 is methyl. Another
group of compounds of Formula I includes compounds wherein R.sub.2
is alkyl, halogenated alkyl, or substituted alkyl. Another group of
compounds of Formula I includes compounds wherein R.sub.2 is alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, or aryl.
[0103] Another group of compounds of Formula I includes compounds
wherein W is CH. Another group of compounds of Formula I includes
compounds wherein W is CH and wherein V--Z--Y is
O--C(R.sub.3).dbd.N, O--C(R.sub.5)(R.sub.3)--N(R.sub.4),
O--C(R.sub.5)(R.sub.3)--S, O--N.dbd.C(R.sub.5),
O--C(R.sub.3)(R.sub.5)--O, S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.- sub.4),
C(R.sub.5).sub.2--O--N(R.sub.4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub.3)(R.sub.5)--C(R.sub.5).sub.2.
[0104] Another group of compounds of Formula I includes compounds
wherein W is CH and wherein V--Z--Y is independently any one of or
combination of O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5), O--C(R.sub.3)(R.sub.5)--O- ,
S--C(R.sub.3).dbd.N, S--C(R.sub.5)(R.sub.3)--N(R.sub.4),
S--N.dbd.C(R.sub.5), N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2, or
C(R.sub.5)(R.sub.17)--C(R.sub.3)(R.sub.17)--C(R.sub.5)(R.sub.17).
[0105] Another group of compounds of Formula I includes compounds
wherein W is CH and wherein V--Z--Y is independently any one of or
combination of O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5), O--C(R.sub.3)(R.sub.8)--O- ,
S--C(R.sub.3).dbd.N, S--C(R.sub.5)(R.sub.3)--N(R.sub.4),
S--N.dbd.C(R.sub.5), N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub.3)(R.sub.5)--C(R.sub.5).sub.2.
[0106] Another group of compounds of Formula I includes compounds
wherein W is CH and wherein V--Z--Y is independently any one of or
combination of O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5), O--C(R.sub.3)(R.sub.8)--O- ,
S--C(R.sub.3).dbd.N, S--C(R.sub.5)(R.sub.3)--N(R.sub.4),
S--N.dbd.C(R.sub.5), N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).sub.2--O--C(R.sub.5).sub.2,
C(R.sub.5).sub.2--S--C(R.sub.5).su- b.2,
C(R.sub.5).sub.2--N(R.sub.4)--C(R.sub.5).sub.2, or
C(R.sub.5)(R.sub.17)--C(R.sub.3)(R.sub.17)--C(R.sub.5)(R.sub.17).
[0107] Another group of compounds of Formula I includes compounds
wherein W is N. Another group of compounds of Formula I includes
compounds wherein W is N and wherein V--Z--Y is independently any
one of or combination of O--C(R.sub.3).dbd.N,
O--C(R.sub.5)(R.sub.3)--N(R.sub.4), O--C(R.sub.5)(R.sub.3)--S,
O--N.dbd.C(R.sub.5) O--C(R.sub.3)(R.sub.5)--O, S--C(R.sub.3).dbd.N,
S--C(R.sub.5)(R.sub.3)--N(R.sub.4), S--N.dbd.C(R.sub.5),
N.dbd.C(R.sub.3)--O, N.dbd.C(R.sub.3)--S,
N.dbd.C(R.sub.3)--N(R.sub.4), N(R.sub.4)--N.dbd.C(R.sub.5),
N(R.sub.4)--C(R.sub.5)(R.sub.3)--O,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--S,
N(R.sub.4)--C(R.sub.5)(R.sub.3)--N(R.sub.4),
C(R.sub.5).sub.2--O--N(R.sub- .4), C(R.sub.5).sub.2--N(R.sub.4)--O,
C(R.sub.5).sub.2--N(R.sub.4)--S, C(R.sub.5).dbd.N--O,
C(R.sub.5).dbd.N--S, C(R.sub.5).dbd.N--N(R.sub.4),
C(R.sub.5).dbd.C(R.sub.3)--C(R.sub.5).sub.2, or
C(R.sub.5).sub.2--C(R.sub- .3)(R.sub.5)--C(R.sub.5).sub.2.
[0108] Another group of compounds of Formula I includes compounds
wherein R.sub.3 is H, F, alkyl, halogenated alkyl, substituted
alkyl, lactam heterocycloalkyl, phenoxy, substituted phenoxy,
R.sub.7, R.sub.9, --N(R.sub.4)-aryl, --O-substituted phenyl,
--O-substituted naphthyl, --S-substituted phenyl, --S-substituted
naphthyl, alkyl substituted on the .omega. carbon with naphthyl, or
alkyl substituted on the .omega. carbon with substituted naphthyl.
Said .omega. carbon is determined by counting the longest carbon
chain of the alkyl moiety with the C-1 carbon being the carbon
attached to the bicyclic moiety W.sup.0 and the .omega. carbon
being the carbon furthest, e.g., separated by the greatest number
of carbon atoms in the chain, from said C-1 carbon. Another group
of compounds of Formula I includes compounds wherein R.sub.3 is H,
F, alkyl, halogenated alkyl, substituted alkyl, lactam
heterocycloalkyl, phenoxy, substituted phenoxy, --N(R.sub.4)-aryl,
--O-substituted phenyl, --O-substituted naphthyl, --S-substituted
phenyl, --S-substituted naphthyl, alkyl substituted on the .omega.
carbon with naphthyl, or alkyl substituted on the .omega. carbon
with substituted naphthyl.
[0109] Another group of compounds of Formula I includes compounds
wherein R.sub.3 is H, F, alkyl, halogenated alkyl, lactam
heterocycloalkyl, phenoxy, substituted phenoxy, R.sub.7, R.sub.9,
--N(R.sub.4)-aryl, --O-substituted phenyl, --O-substituted
naphthyl, --S-substituted phenyl, --S-substituted naphthyl, or or
alkyl substituted on the .omega. carbon with R.sub.15. Another
group of compounds of Formula I includes compounds wherein R.sub.3
is H, F, alkyl, halogenated alkyl, lactam heterocycloalkyl,
phenoxy, substituted phenoxy, --N(R.sub.4)-aryl, --O-substituted
phenyl, --O-substituted naphthyl, --S-substituted phenyl,
--S-substituted naphthyl, or alkyl substituted on the .omega.
carbon with R.sub.15.
[0110] Another group of compounds of Formula I includes compounds
wherein R.sub.5 is H, F, Br, Cl, I, alkyl, substituted alkyl,
halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl,
heterocycloalkyl, substituted heterocycloalkyl, lactam
heterocycloalkyl, --CN, --NO.sub.2, --OR.sub.1,
--C(O)N(R.sub.16).sub.2, --NHR.sub.1, --NR.sub.1COR.sub.16,
--N(R.sub.10).sub.2, --SR.sub.1, --C(O)R.sub.16, --CO.sub.2R.sub.1,
aryl, R.sub.7, or R.sub.9. Another group of compounds of Formula I
includes compounds wherein R.sub.5 is H, F, Br, Cl, alkyl,
substituted alkyl, halogenated alkyl, alkenyl, substituted alkenyl,
halogenated alkenyl, alkynyl, substituted alkynyl, halogenated
alkynyl, heterocycloalkyl, substituted heterocycloalkyl, lactam
heterocycloalkyl, --CN, --NO.sub.2, --OR.sub.1,
--C(O)N(R.sub.16).sub.2, --NHR.sub.1, --NR.sub.1COR.sub.16,
--N(R.sub.10).sub.2, --SR.sub.1.
[0111] Another group of compounds of Formula I includes compounds
wherein R.sub.6 is any one of or combination of H, F, Cl, Br, I,
--CN, --CF.sub.3, --OR.sub.16, --SR.sub.16, or --N(R.sub.16).sub.2.
Another group of compounds of Formula I includes compounds wherein
R.sub.6 is any one of or combination of H, F, Cl, Br, --CN,
--CF.sub.3, --OR.sub.16, --SR.sub.16, or --N(R.sub.16).sub.2.
[0112] Another group of compounds of Formula I includes compounds
wherein R.sub.17 is any one of or combination of H, F, Br, Cl, I,
alkyl, substituted alkyl, halogenated alkyl, alkenyl, substituted
alkenyl, halogenated alkenyl, alkynyl, substituted alkynyl,
halogenated alkynyl, --CN, --OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1,
--SR.sub.1, --CO.sub.2R.sub.1, aryl, R.sub.7, or R.sub.9. Another
group of compounds of Formula I includes compounds wherein R.sub.17
is any one of or combination of H, F, Br, Cl, alkyl, substituted
alkyl, halogenated alkyl, alkenyl, substituted alkenyl, halogenated
alkenyl, alkynyl, substituted alkynyl, halogenated alkynyl, --CN,
--OR.sub.1, --C(O)NH.sub.2, --NHR.sub.1, --SR.sub.1.
[0113] Another group of compounds of Formula I includes compounds
wherein R.sub.21 is any one of or combination of H, F, Cl, Br, I,
alkyl, substituted alkyl, halogenated alkyl, cycloalkyl, --CN,
--NR.sub.22R.sub.22, --OR.sub.22, or --SR.sub.22. Another group of
compounds of Formula I includes compounds wherein R.sub.21 is any
one of or combination of H, F, Cl, Br, alkyl, substituted alkyl,
halogenated alkyl, --CN, --N(R.sub.22).sub.2, --OR.sub.22, or
--SR.sub.22.
[0114] Another group of compounds of Formula I includes compounds
wherein R.sub.23 is any one of or combination of H, alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, halogenated
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated
heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl,
naphthyl, substituted naphthyl, R.sub.7, or R.sub.9. Another group
of compounds of Formula I includes compounds wherein R.sub.23 is
any one of or combination of H, alkyl, halogenated alkyl,
substituted alkyl, heterocycloalkyl, or substituted
heterocycloalkyl.
[0115] Another group of compounds of Formula I includes compounds
wherein W.sup.0 is 13
[0116] wherein W, R.sub.6, and V--Z--Y are defined herein.
[0117] Another group of compounds of Formula I includes compounds
wherein W.sup.0 is 14
[0118] wherein Q and R.sub.6 are defined herein.
[0119] Another group of compounds of Formula I for treating the
diseases or conditions discussed herein includes compounds wherein
W.sup.0 is 15
[0120] wherein W.sup.1, W.sup.2, W.sup.3, W.sup.1 are each
independently N or C(R.sub.21), provided that no more than two of
W.sup.1, W.sup.2, W.sup.3, W.sup.4 are N, and further provided when
more than two of W.sup.1, W.sup.2, W.sup.3, W.sup.1 are C(R.sub.21)
that no more than two R.sub.2, are other than H; and wherein J is
N(R.sub.23), S, or O.
[0121] Another group of compounds of Formula I includes compounds
wherein W.sup.0 is 16
[0122] wherein W.sup.1, W.sup.2, W.sup.3, W.sup.1 are each
independently N or C(R.sub.21), provided that no more than two of
W.sup.1, W.sup.2, W.sup.3, W.sup.4 are N, further provided that
when J is N(R.sub.23), at least one of W.sup.1, W.sup.2, W.sup.3,
W.sup.4 is N, and further provided when more than two of W.sup.1,
W.sup.2, W W.sup.4 are C(R.sub.21) that no more than two R.sub.21
are other than H; and wherein J is N(R.sub.23), S, or O.
[0123] Another group of compounds of Formula I includes compounds
wherein W.sup.0 is 17
[0124] wherein W.sup.1, W.sup.2, W.sup.3, W.sup.4 are each
independently N or C(R.sub.21), provided that no more than two of
W.sup.1, W.sup.2, W.sup.3, W.sup.4 are N, and further provided when
more than two of W.sup.1, W.sup.2, W.sup.3, W.sup.4 are C(R.sub.21)
that no more than two R.sub.21 are other than H; and wherein J is
S, or O.
[0125] Another group of compounds of Formula I includes compounds
wherein W.sup.0 includes any one of or combination of the
following:
[0126] 1,3-benzoxazol-6-yl, 1,3-benzoxazol-5-yl,
1,3-benzothiazol-6-yl, indan-5-yl, 1,3-benzodioxol-5-yl,
[1,3]oxazolo[5,4-c]pyridin-6-yl, 2-benzoisothiophen-5-yl,
1,3-benzothiazol-5-yl, 1,3-benzothiazol-2-yl,
1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-5-yl,
3H-imidazo[4,5-b]pyridin-2-- yl, or 1H-indazol-6-yl, optionally
substituted with F, Br, Cl, alkyl, halogenated alkyl, substituted
alky, alkyl substituted on the .omega. carbon with R.sub.15,
alkenyl, substituted alkenyl, halogenated alkenyl, alkynyl,
substituted alkynyl, halogenated alkynyl, heterocycloalkyl,
substituted heterocycloalkyl, lactam heterocycloalkyl, phenoxy,
substituted phenoxy, --CF.sub.3, --CN, --NO.sub.2, --OR.sub.1,
--OR.sub.16, --OR.sub.22, --O-substituted phenyl, --O-substituted
naphthyl, --NHR.sub.1, --N(R.sub.10).sub.2, --N(R.sub.16).sub.2,
--N(R.sub.22).sub.2, --N(R.sub.4)-aryl, --SR.sub.1, --SR.sub.16,
--SR.sub.22, --S-substituted phenyl, --S-substituted naphthyl,
--C(O)N(R.sub.16).sub.2, --NR.sub.1COR.sub.16. One of ordinary
skill in the art will recognize where the optional substitution is
allowed by comparing the listed moieties with W.sup.0 and
identifying where R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.17,
R.sub.21 and R.sub.23 would allow for substitution.
[0127] Another group of compounds of Formula I includes any one of
or combination of the following:
[0128] N-((3R)-1 -azabicyclo[2.2.2]oct-3-yl)-
1,3-benzoxazole-6-carboxamid- e;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxam-
ide;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamid-
e;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide;
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide;
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo
[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carbox- amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxam-
ide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-ca-
rboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1
,3-benzothiazole-2-carbox- amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-ca-
rboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazol-
e-6-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-
-1,3-benzoxazole-6-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-
-3-yl)-1,3-benzoxazole-5-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2-
.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carb-
oxamide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxam-
ide;
N-((2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-c-
arboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5-
,4-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3--
yl]-2-benzoisothiophene-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.-
2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabi-
cyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazo-
le-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-inda-
zole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-b-
enzothiazole-2-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-y-
l]-6-fluoro-1,3-benzothiazole-2-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicy-
clo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-carboxamide; or a
pharmaceutically acceptable salt or pharmaceutical composition
thereof.
[0129] Another group of compounds of Formula I includes any one of
or combination of the following:
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-be-
nzoxazole-6-carboxamide;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3--
benzoxazole-6-carboxamide;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxa-
zole-5-carboxamide;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzo-
xazole-5-carboxamide;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazol-
e-6-carboxamide;
N-((3S)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide;
N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxa-
mide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxami-
de;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxa-
mide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-ca-
rboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carboxamide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1,3-benzothiazole-2-carboxa-
mide;
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-car-
boxamide; or a pharmaceutically acceptable salt or pharmaceutical
composition thereof.
[0130] Another group of compounds of Formula I includes any one of
or combination of the following:
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-ind- azole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-inda-
zole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1H-indaz-
ole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazol-
e-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole--
5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-6--
carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,2-benzisothiazole-5-ca-
rboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazol-
e-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisot-
hiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-b-
enzisothiazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methy-
l-1,2-benzisothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]--
2-cyclopropyl-1,3-benzoxazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oc-
t-3-yl]-2-cyclopropyl-1,3-benzoxazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-ca-
rboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothi-
azole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,3-ben-
zothiazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1,-
3-benzothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-ethy-
l-1,3-benzothiazole-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2--
ethyl-1,3-benzothiazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl-
]-2-methyl-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct--
3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]o-
ct-3-yl]-2,2-dimethyl-1,3-benzodioxole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2H-isoindole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzimidazole-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[5,4-c]pyridine-6-carbox-
amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyridine-6--
carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]dioxolo[4,5-c]pyridi-
ne-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[4,5-c]p-
yridine-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-
-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl-
]-1H-indazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3--
yl]-1H-indazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct--
3-yl]-3-methyl-1H-indazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo-
[2.2.2]oct-3-yl]-3-methyl-1H-indazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-indazole-6-ca-
rboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1H-ind-
azole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,2--
benzisothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct--
3-yl]-1,2-benzisothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[-
2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethyl-1,2-benzisothiaz-
ole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-meth-
yl-1,2-benzisothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2-
.2]oct-3-yl]-3-methyl-1,2-benzisothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzox-
azole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cy-
clopropyl-1,3-benzoxazole-5-carboxamide; N-[(2S
,3R)-2-methyl-1-azabicyclo-
[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyclopropyl-1,3-benzot-
hiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2--
methyl-1,3-benzothiazole-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2-
.2.2]oct-3-yl]-2-methyl-1,3-benzothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzothiazol-
e-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-ethyl--
1,3-benzothiazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oc-
t-3-yl]-2-methyl-1,3-benzodioxole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-aza-
bicyclo[2.2.2]oct-3-yl]-2-ethyl-1,3-benzodioxole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2,2-dimethyl-1,3-benzodi-
oxole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-be-
nzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-
H-isoindole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl-
]-1H-benzimidazole-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]o-
ct-3-yl][1,3]thiazolo[5,4-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]thiazolo[4,5-c]pyrid-
ine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl][1,3]di-
oxolo[4,5-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2-
]oct-3-yl][1,3]oxazolo[4,5-c]pyridine-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1H-imidazo[4,5-c]pyridin-
e-6-carboxamide; or a pharmaceutically acceptable salt or
pharmaceutical composition thereof.
[0131] Abbreviations which are well known to one of ordinary skill
in the art may be used (e.g., "Ph" for phenyl, "Me" for methyl,
"Et" for ethyl, "h" or "hr" for hour or hours, min for minute or
minutes, and "rt" or "RT" for room temperature).
[0132] All temperatures are in degrees Centigrade.
[0133] Room temperature is within the range of 15-25 degrees
Celsius.
[0134] AChR refers to acetylcholine receptor.
[0135] nAChR refers to nicotinic acetylcholine receptor.
[0136] Pre-senile dementia is also known as mild cognitive
impairment.
[0137] 5HT.sub.3R refers to the serotonin-type 3 receptor.
[0138] .alpha.-btx refers to .alpha.-bungarotoxin.
[0139] FLIPR refers to a device marketed by Molecular Devices, Inc.
designed to precisely measure cellular fluorescence in a high
throughput whole-cell assay. (Schroeder et. al., J. Biomolecular
Screening, 1(2), p 75-80, 1996).
[0140] TLC refers to thin-layer chromatography.
[0141] HPLC refers to high pressure liquid chromatography.
[0142] MeOH refers to methanol.
[0143] EtOH refers to ethanol.
[0144] IPA refers to isopropyl alcohol.
[0145] THF refers to tetrahydrofuran.
[0146] DMSO refers to dimethylsulfoxide.
[0147] DMF refers to N,N-dimethylformamide.
[0148] EtOAc refers to ethyl acetate.
[0149] TMS refers to tetramethylsilane.
[0150] TEA refers to triethylamine.
[0151] DIEA refers to N,N-diisopropylethylamine.
[0152] MLA refers to methyllycaconitine.
[0153] Ether refers to diethyl ether.
[0154] HATU refers to 0-(7-azabenzotriazol-1-yl)--N,N,N',
N'-tetramethyluronium hexafluorophosphate.
[0155] CDI refers to carbonyl diimidazole.
[0156] NMO refers to N-methylmorpholine-N-oxide.
[0157] TPAP refers to tetrapropylammonium perruthenate.
[0158] Halogen is F, Cl, Br, or I.
[0159] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum number of carbon atoms in the moiety, i.e., the prefix
C.sub.i-j indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive. Thus, for example, C.sub.1-6 alkyl refers
to alkyl of one to six carbon atoms.
[0160] Non-inclusive examples of heteroaryl compounds that fall
within the definition of R.sub.7 and R.sub.9 include, but are not
limited to, thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl,
pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl,
benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, indolyl, benzoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pydridazinyl,
triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl,
benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, naphthridinyl, and furopyridinyl.
[0161] Non-inclusive examples of heterocycloalkyl include, but are
not limited to, tetrahydrofurano, tetrahydropyrano, morpholino,
pyrrolidino, piperidino, piperazine, azetidino, azetidinono,
oxindolo, dihydroimidazolo, and pyrrolidinono.
[0162] The .omega. carbon with R.sub.15 is determined by counting
the longest carbon chain of the alkyl moiety with the C-1 carbon
being the carbon attached to the bicyclic moiety W.sup.0 and the
.omega. carbon being the .omega. carbon furthest, e.g., separated
by the greatest number of carbon atoms in the chain, from said C-1
carbon.
[0163] The core molecule is the quinuclidinyl-(carboxamide-type
moiety)-W.sup.0: 18
[0164] Therefore, when determining the .omega. carbon, the C-1
carbon will be the carbon attached, as valency allows, to the
W.sup.0 moiety of the core molecule and the .omega. carbon will be
the carbon furthest from said C-1 carbon.
[0165] Mammal denotes human and other mammals.
[0166] Brine refers to an aqueous saturated sodium chloride
solution.
[0167] Equ means molar equivalents.
[0168] IR refers to infrared spectroscopy.
[0169] Lv refers to leaving groups within a molecule, including Cl,
OH, or mixed anhydride.
[0170] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (.delta.)
downfield from TMS.
[0171] MS refers to mass spectrometry expressed as m/e or
mass/charge unit. HRMS refers to high resolution mass spectrometry
expressed as m/e or mass/charge unit. M+H.sup.+ refers to the
positive ion of a parent plus a hydrogen atom. M-H.sup.- refers to
the negative ion of a parent minus a hydrogen atom. M+Na.sup.+
refers to the positive ion of a parent plus a sodium atom.
M+K.sup.+ refers to the positive ion of a parent plus a potassium
atom. EI refers to electron impact. ESI refers to electrospray
ionization. CI refers to chemical ionization. FAB refers to fast
atom bombardment.
[0172] Compounds of the present invention may be in the form of
pharmaceutically acceptable salts. The term "pharmaceutically
acceptable salts" refers to salts prepared from pharmaceutically
acceptable non-toxic bases including inorganic bases and organic
bases, and salts prepared from inorganic acids, and organic acids.
Salts derived from inorganic bases include aluminum, ammonium,
calcium, ferric, ferrous, lithium, magnesium, potassium, sodium,
zinc, and the like. Salts derived from pharmaceutically acceptable
organic non-toxic bases include salts of primary, secondary, and
tertiary amines, substituted amines including naturally occurring
substituted amines, cyclic amines, such as arginine, betaine,
caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, and the like. Salts derived from
inorganic acids include salts of hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous
acid and the like. Salts derived from pharmaceutically acceptable
organic non-toxic acids include salts of C.sub.1-6 alkyl carboxylic
acids, di-carboxylic acids, and tri-carboxylic acids such as acetic
acid, propionic acid, fumaric acid, succinic acid, tartaric acid,
maleic acid, adipic acid, and citric acid, and aryl and alkyl
sulfonic acids such as toluene sulfonic acids and the like.
[0173] By the term "effective amount" of a compound as provided
herein is meant a nontoxic but sufficient amount of the compound(s)
to provide the desired effect. As pointed out below, the exact
amount required will vary from subject to subject, depending on the
species, age, and general condition of the subject, the severity of
the disease that is being treated, the particular compound(s) used,
the mode of administration, and the like. Thus, it is not possible
to specify an exact "effective amount." However, an appropriate
effective amount may be determined by one of ordinary skill in the
art using only routine experimentation.
[0174] The compounds of Formula I have optically active center(s)
on the quinuclidine ring. Although it is desirable that the
stereochemical purity be as high as possible, absolute purity is
not required. This invention involves racemic mixtures and
compositions of varying degrees of stereochemical purities. It is
preferred to carry out stereoselective syntheses and/or to subject
the reaction product to appropriate purification steps so as to
produce substantially optically pure materials. Suitable
stereoselective synthetic procedures for producing optically pure
materials are well known in the art, as are procedures for
purifying racemic mixtures into optically pure fractions.
[0175] The amount of therapeutically effective compound(s) that is
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular
compound(s) employed, and thus may vary widely. The compositions
contain well know carriers and excipients in addition to a
therapeutically effective amount of compounds of Formula I. The
pharmaceutical compositions may contain active ingredient in the
range of about 0.001 to 100 mg/kg/day for an adult, preferably in
the range of about 0.1 to 50 mg/kg/day for an adult. A total daily
dose of about 1 to 1000 mg of active ingredient may be appropriate
for an adult. The daily dose can be administered in one to four
doses per day.
[0176] In addition to the compound(s) of Formula I, the composition
for therapeutic use may also comprise one or more non-toxic,
pharmaceutically acceptable carrier materials or excipients. The
term "carrier" material or "excipient" herein means any substance,
not itself a therapeutic agent, used as a carrier and/or diluent
and/or adjuvant, or vehicle for delivery of a therapeutic agent to
a subject or added to a pharmaceutical composition to improve its
handling or storage properties or to permit or facilitate formation
of a dose unit of the composition into a discrete article such as a
capsule or tablet suitable for oral administration. Excipients can
include, by way of illustration and not limitation, diluents,
disintegrants, binding agents, adhesives, wetting agents, polymers,
lubricants, glidants, substances added to mask or counteract a
disagreeable taste or odor, flavors, dyes, fragrances, and
substances added to improve appearance of the composition.
Acceptable excipients include lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl
alcohol, and then tableted or encapsulated for convenient
administration. Such capsules or tablets may contain a
controlled-release formulation as may be provided in a dispersion
of active compound in hydroxypropyl-methyl cellulose, or other
methods known to those skilled in the art. For oral administration,
the pharmaceutical composition may be in the form of, for example,
a tablet, capsule, suspension or liquid. If desired, other active
ingredients may be included in the composition.
[0177] In addition to the oral dosing, noted above, the
compositions of the present invention may be administered by any
suitable route, in the form of a pharmaceutical composition adapted
to such a route, and in a dose effective for the treatment
intended. The compositions may, for example, be administered
parenterally, e.g., intravascularly, intraperitoneally,
subcutaneously, or intramuscularly. For parenteral administration,
saline solution, dextrose solution, or water may be used as a
suitable carrier. Formulations for parenteral administration may be
in the form of aqueous or non-aqueous isotonic sterile injection
solutions or suspensions. These solutions and suspensions may be
prepared from sterile powders or granules having one or more of the
carriers or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed
oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,
and/or various buffers. Other adjuvants and modes of administration
are well and widely known in the pharmaceutical art.
[0178] The serotonin type 3 receptor (5HT.sub.3R) is a member of a
superfamily of ligand-gated ion channels, which includes the muscle
and neuronal nAChR, the glycine receptor, and the
.gamma.-aminobutyric acid type A receptor. Like the other members
of this receptor superfamily, the 5HT.sub.3R exhibits a large
degree of sequence homology with .alpha.7 nAChR but functionally
the two ligand-gated ion channels are very different. For example,
.alpha.7 nAChR is rapidly inactivated, is highly permeable to
calcium and is activated by acetylcholine and nicotine. On the
other hand, 5HT.sub.3R is inactivated slowly, is relatively
impermeable to calcium and is activated by serotonin. These
experiments suggest that the .alpha.7 nAChR and 5HT.sub.3R proteins
have some degree of homology, but function very differently. Indeed
the pharmacology of the channels is very different. For example,
Ondansetron, a highly selective 5HT.sub.3R antagonist, has little
activity at the .alpha.7 nAChR. The converse is also true. For
example, GTS-21, a highly selective .alpha.7 nAChR agonist, has
little activity at the 5HT.sub.3R.
[0179] .alpha.7 nAChR is a ligand-gated Ca.sup.++ channel formed by
a homopentamer of .alpha.7 subunits. Previous studies have
established that .alpha.-bungarotoxin (a-btx) binds selectively to
this homopetameric, .alpha.7 nAChR subtype, and that .alpha.7 nAChR
has a high affinity binding site for both .alpha.-btx and
methyllycaconitine (MLA). .alpha.7 nAChR is expressed at high
levels in the hippocampus, ventral tegmental area and ascending
cholinergic projections from nucleus basilis to thalamocortical
areas. .alpha.7 nAChR agonists increase neurotransmitter release,
and increase cognition, arousal, attention, learning and
memory.
[0180] Data from human and animal pharmacological studies establish
that nicotinic cholinergic neuronal pathways control many important
aspects of cognitive function including attention, learning and
memory (Levin, E. D., Psychopharmacology, 108:417-31, 1992; Levin,
E. D. and Simon B. B., Psychopharmacology, 138:217-30, 1998). For
example, it is well known that nicotine increases cognition and
attention in humans. ABT-418, a compound that activates
.alpha.:4.beta.2 and (.alpha.7 nAChR, improves cognition and
attention in clinical trials of Alzheimer's disease and
attention-deficit disorders (Potter, A. et. al., Psychopharmacology
(Berl)., 142(4):334-42, March 1999; Wilens, T. E. et. al., Am. J.
Psychiatry, 156(12):1931-7, December 1999). It is also clear that
nicotine and selective but weak .alpha.7 nAChR agonists increase
cognition and attention in rodents and non-human primates.
[0181] Schizophrenia is a complex multifactorial illness caused by
genetic and non-genetic risk factors that produce a constellation
of positive and negative symptoms. The positive symptoms include
delusions and hallucinations and the negative symptoms include
deficits in affect, attention, cognition and information
processing. No single biological element has emerged as a dominant
pathogenic factor in this disease. Indeed, it is likely that
schizophrenia is a syndrome that is produced by the combination of
many low penetrance risk factors. Pharmacological studies
established that dopamine receptor antagonists are efficacious in
treating the overt psychotic features (positive symptoms) of
schizophrenia such as hallucinations and delusions. Clozapine, an
"atypical" antipsychotic drug, is novel because it is effective in
treating both the positive and some of the negative symptoms of
this disease. Clozapine's utility as a drug is greatly limited
because continued use leads to an increased risk of agranulocytosis
and seizure. No other antipsychotic drug is effective in treating
the negative symptoms of schizophrenia. This is significant because
the restoration of cognitive functioning is the best predictor of a
successful clinical and functional outcome of schizophrenic
patients (Green, M. F., Am J Psychiatry, 153:321-30, 1996). By
extension, it is clear that better drugs are needed to treat the
cognitive disorders of schizophrenia in order to restore a better
state of mental health to patients with this disorder.
[0182] One aspect of the cognitive deficit of schizophrenia can be
measured by using the auditory event-related potential (P50) test
of sensory gating. In this test, electroencepholographic (EEG)
recordings of neuronal activity of the hippocampus are used to
measure the subject's response to a series of auditory "clicks"
(Adler, L. E. et. al., Biol. Psychiatry, 46:8-18, 1999). Normal
individuals respond to the first click with greater degree than to
the second click. In general, schizophrenics and schizotypal
patients respond to both clicks nearly the same (Cullum, C. M. et.
al., Schizophr. Res., 10:131-41, 1993). These data reflect a
schizophrenic's inability to "filter" or ignore unimportant
information. The sensory gating deficit appears to be one of the
key pathological features of this disease (Cadenhead, K. S. et.
al., Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that
nicotine normalizes the sensory deficit of schizophrenia (Adler, L.
E. et. al., Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological
studies indicate that nicotine's effect on sensory gating is via
the .alpha.7 nAChR (Adler, L. E. et. al., Schizophr. Bull.,
24:189-202, 1998). Indeed, the biochemical data indicate that
schizophrenics have 50% fewer of (.alpha.7 nAChR receptors in the
hippocampus, thus giving a rationale to partial loss of (.alpha.7
nAChR functionality (Freedman, R. et. al., Biol. Psychiatry,
38:22-33, 1995). Interestingly, genetic data indicate that a
polymorphism in the promoter region of the .alpha.7 nAChR gene is
strongly associated with the sensory gating deficit in
schizophrenia (Freedman, R. et. al., Proc. Nat'l Acad. Sci. USA,
94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med. Genet,
88(5):544-50, 1999). To date, no mutation in the coding region of
the .alpha.7 nAChR has been identified. Thus, schizophrenics
express the same .alpha.7 nAChR as non-schizophrenics.
[0183] Selective .alpha.7 nAChR agonists may be found using a
functional assay on FLIPR (see WO 00/73431 A2). FLIPR is designed
to read the fluorescent signal from each well of a 96 or 384 well
plate as fast as twice a second for up to 30 minutes. This assay
may be used to accurately measure the functional pharmacology of
.alpha.7 nAChR and 5HT.sub.3R. To conduct such an assay, one uses
cell lines that expressed functional forms of the .alpha.7 nAChR
using the .alpha.7/5-HT.sub.3 channel as the drug target and cell
lines that expressed functional 5HT.sub.3R. In both cases, the
ligand-gated ion channel was expressed in SH-EP1 cells. Both ion
channels can produce robust signal in the FLIPR assay.
[0184] The compounds of the present invention are .alpha.7 nAChR
agonists and may be used to treat a wide variety of diseases. For
example, they may be used in treating schizophrenia, or
psychosis.
[0185] Schizophrenia is a disease having multiple aspects.
Currently available drugs are generally aimed at controlling the
positive aspects of schizophrenia, such as delusions. One drug,
Clozapine, is aimed at a broader spectrum of symptoms associated
with schizophrenia. This drug has many side effects and is thus not
suitable for many patients. Thus, there is a need for a drug to
treat the cognitive and attention deficits associated with
schizophrenia. Similarly, there is a need for a drug to treat the
cognitive and attention deficits associated with schizoaffective
disorders, or similar symptoms found in the relatives of
schizophrenic patients.
[0186] Psychosis is a mental disorder characterized by gross
impairment in the patient's perception of reality. The patient may
suffer from delusions, and hallucinations, and may be incoherent in
speech. His behavior may be agitated and is often incomprehensible
to those around him. In the past, the term psychosis has been
applied to many conditions that do not meet the stricter definition
given above. For example, mood disorders were named as
psychoses.
[0187] There are a variety of antipsychotic drugs. The conventional
antipsychotic drugs include Chlorpromazine, Fluphenazine,
Haloperidol, Loxapine, Mesoridazine, Molindone, Perphenazine,
Pimozide, Thioridazine, Thiothixene, and Trifluoperazine. These
drugs all have an affinity for the dopamine 2 receptor.
[0188] These conventional antipsychotic drugs have several side
effects, including sedation, weight gain, tremors, elevated
prolactin levels, akathisia (motor restlessness), dystonia and
muscle stiffness. These drugs may also cause tardive dyskinesia.
Unfortunately, only about 70% of patients with schizophrenia
respond to conventional antipsychotic drugs. For these patients,
atypical antipsychotic drugs are available.
[0189] Atypical antipsychotic drugs generally are able to alleviate
positive symptoms of psychosis while also improving negative
symptoms of the psychosis to a greater degree than conventional
antipsychotics. These drugs may improve neurocognitive deficits.
Extrapyramidal (motor) side effects are not as likely to occur with
the atypical antipsychotic drugs, and thus, these atypical
antipsychotic drugs have a lower risk of producing tardive
dyskinesia. Finally these atypical antipsychotic drugs cause little
or no elevation of prolactin. Unfortunately, these drugs are not
free of side effects. Although these drugs each produce different
side effects, as a group the side effects include: agranulocytosis;
increased risk of seizures, weight gain, somnolence, dizziness,
tachycardia, decreased ejaculatory volume, and mild prolongation of
QTc interval.
[0190] In a combination therapy to treat multiple symptoms of
diseases such as schizophrenia, the compounds of Formula I and the
anti-psychotic drugs can be administered simultaneously or at
separate intervals. When administered simultaneously the compounds
of Formula I and the anti-psychotic drugs can be incorporated into
a single pharmaceutical composition, e.g., a pharmaceutical
combination therapy composition. Alternatively, two separate
compositions, i.e., one containing compounds of Formula I and the
other containing anti-psychotic drugs, can be administered
simultaneously. Examples of anti-psychotic drugs, in addition to
those listed above, include, but are not limited to, Thorazine,
Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin,
Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine,
Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone,
Ondansetron, Pimozide, Prochlorperazine, and Promazine.
[0191] A pharmaceutical combination therapy composition can include
therapeutically effective amounts of the compounds of Formula I,
noted above, and a therapeutically effective amount of
anti-psychotic drugs. These compositions may be formulated with
common excipients, diluents or carriers, and compressed into
tablets, or formulated elixirs or solutions for convenient oral
administration or administered by intramuscular intravenous routes.
The compounds can be administered rectally, topically, orally,
sublingually, or parenterally and maybe formulated as sustained
relief dosage forms and the like.
[0192] When separately administered, therapeutically effective
amounts of compositions containing compounds of Formula I and
anti-psychotic drugs are administered on a different schedule. One
may be administered before the other as long as the time between
the two administrations falls within a therapeutically effective
interval. A therapeutically effective interval is a period of time
beginning when one of either (a) the compounds of Formula I, or (b)
the anti-psychotic drugs is administered to a human and ending at
the limit of the beneficial effect in the treatment of
schizophrenia or psychosis of the combination of (a) and (b). The
methods of administration of the compounds of Formula I and the
anti-psychotic drugs may vary. Thus, either agent or both agents
may be administered rectally, topically, orally, sublingually, or
parenterally.
[0193] As discussed, the compounds of the present invention are
.alpha.7 nAChR agonists. Therefore, as another aspect of the
present invention, the compounds of the present invention may be
used to treat a variety of diseases including cognitive and
attention deficit symptoms of Alzheimer's, neurodegeneration
associated with diseases such as Alzheimer's disease, pre-senile
dementia (also known as mild cognitive impairment), and senile
dementia.
[0194] Alzheimer's disease has many aspects, including cognitive
and attention deficits. Currently, these deficits are treated with
cholinesterase inhibitors. These inhibitors slow the break down of
acetylcholine, and thereby provide a general nonspecific increase
in the activity of the cholinergic nervous system. Since the drugs
are nonspecific, they have a wide variety of side effects. Thus,
there is a need for a drug that stimulates a portion of the
cholinergic pathways and thereby provides improvement in the
cognitive and attention deficits associated with Alzheimer's
disease without the side effects created by nonspecific stimulation
of the cholinergic pathways.
[0195] Neurodegeneration is a common problem associated with
diseases such as Alzheimer's disease. While the current drugs treat
some of the symptoms of this disease, they do not control the
underlying pathology of the disease. Accordingly, it would be
desirable to provide a drug that can slow the progress of
Alzheimer's disease.
[0196] Pre-senile dementia (mild cognitive impairment) concerns
memory impairment rather than attention deficit problems and
otherwise unimpaired cognitive functioning. Mild cognitive
impairment is distinguished from senile dementia in that mild
cognitive impairment involves a more persistent and troublesome
problem of memory loss for the age of the patient. There currently
is no medication specifically identified for treatment of mild
cognitive impairment, due somewhat to the newness of identifying
the disease. Therefore, there is a need for a drug to treat the
memory problems associated with mild cognitive impairment.
[0197] Senile dementia is not a single disease state. However, the
conditions classified under this name frequently include cognitive
and attention deficits. Generally, these deficits are not treated.
Accordingly, there is a need for a drug that provides improvement
in the cognitive and attention deficits associated with senile
dementia.
[0198] As discussed, the compounds of the present invention are
.alpha.7 nAChR agonists. Therefore, yet other diseases to be
treated with compounds of the present invention include treating
the cognitive and attention deficits as well as the
neurodegeneration associated with attention deficit disorder,
attention deficit hyperactivity disorder, mood and affective
disorders, amyotrophic lateral sclerosis, borderline personality
disorder, traumatic brain injury, behavioral and cognitive problems
associated with brain tumors, AIDS dementia complex, dementia
associated with Down's syndrome, dementia associated with Lewy
Bodies, Huntington's disease, depression, general anxiety disorder,
age-related macular degeneration, Parkinson's disease, tardive
dyskinesia, Pick's disease, post traumatic stress disorder,
dysregulation of food intake including bulemia and anorexia
nervosa, withdrawal symptoms associated with smoking cessation and
dependant drug cessation, Gilles de la Tourette's Syndrome,
glaucoma, or symptoms associated with pain.
[0199] Attention deficit disorder is generally treated with
methylphenidate, an amphetamine-like molecule that has some
potential for abuse. Accordingly, it would be desirable to provide
a drug that treats attention deficit disorder while having fewer
side effects than the currently used drug.
[0200] Attention deficit hyperactivity disorder, otherwise known as
ADHD, is a neurobehavioral disorder affecting 3-5% of all American
children. ADHD concerns cognitive alone or both cognitive and
behavioral actions by interfering with a person's ability to stay
on a task and to exercise age-appropriate inhibition. Several types
of ADHD exist: a predominantly inattentive subtype, a predominantly
hyperactive-impulsive subtype, and a combined subtype. Treatment
may include medications such as methylphenidate, dextroamphetamine,
or pemoline, which act to decrease impulsivity and hyperactivity
and to increase attention. No "cure" for ADHD currently exists.
Children with the disorder seldom outgrow it; therefore, there is a
need for appropriate medicaments.
[0201] Mood and affective disorders fall within a large group of
diseases, including monopolar depression and bi-polar mood
disorder. These diseases are treated with three major classes of
compounds. The first group is the heterocyclic antidepressant
(HCA's). This group includes the well-known tricyclic
antidepressants. The second group of compounds used to treat mood
disorders is the monoamine oxidase inhibitors (MAOI's) that are
used in particular types of diseases. The third drug is lithium.
Common side effects from HCA's are sedation and weight gain. In
elderly patients with organic brain disease, the side effects of
HCA's can also include seizures and behavioral symptoms. The main
side effects from using MAOI's occur from dietary and drug
interactions. Benign side effects from the use of lithium include,
but are not limited to, weight gain, nausea, diarrhea, polyuria,
polydipsia, and tremor. Toxic side effects from lithium can include
persistent headache, mental confusion, and may reach seizures and
cardiac arrhythmias. Therefore, agents with less side effects or
interactions with food or other medications would be useful.
[0202] Depression is a mood disorder of varying lengths of normally
several months to more than two years and of varying degrees of
feelings involving sadness, despair, and discouragement. The
heterocyclic antidepressants (HCA's) are currently the largest
class of antidepressants, but monoamine oxidase inhibitors (MAOI's)
are used in particular types of depression. Common side effects
from HCA's are sedation and weight gain. In elderly patients with
organic brain disease, the side effects from HCA's can also include
seizures and behavioral symptoms. The main side effects from using
MAOI's occur from dietary and drug interactions. Therefore, agents
with fewer side effects would be useful.
[0203] Borderline personality disorder, although not as well known
as bipolar disorder, is more common. People having borderline
personality disorder suffer from a disorder of emotion regulation.
Pharmaceutical agents are used to treat specific symptoms, such as
depression or thinking distortions.
[0204] Acquired immune deficiency syndrome (AIDS) results from an
infection with the human immunodeficiency virus (HIV). This virus
attacks selected cells and impairs the proper function of the
immune, nervous, and other systems. HIV infection can cause other
problems such as, but not limited to, difficulties in thinking,
otherwise known as AIDS dementia complex. Therefore, there is a
need to drugs to relieve the confusion and mental decline of
persons with AIDS.
[0205] Amyotrophic lateral sclerosis, also known as Lou Gehrig's
disease, belongs to a class of disorders known as motor neuron
diseases wherein specific nerve cells in the brain and spinal cord
gradually degenerate to negatively affect the control of voluntary
movement. Currently, there is no cure for amyotrophic lateral
sclerosis although patients may receive treatment from some of
their symptoms and although Riluzole has been shown to prolong the
survival of patients. Therefore, there is a need for a
pharmaceutical agent to treat this disease.
[0206] Traumatic brain injury occurs when the brain is damaged from
a sudden physical assault on the head. Symptoms of the traumatic
brain injury include confusion and other cognitive problems.
Therefore, there is a need to address the symptoms of confusion and
other cognitive problems.
[0207] Brain tumors are abnormal growths of tissue found inside of
the skull. Symptoms of brain tumors include behavioral and
cognitive problems. Surgery, radiation, and chemotherapy are used
to treat the tumor, but other agents are necessary to address
associated symptoms. Therefore, there is a need to address the
symptoms of behavioral and cognitive problems.
[0208] Persons with Down's syndrome have in all or at least some of
their cells an extra, critical portion of the number 21 chromosome.
Adults who have Down's syndrome are known to be at risk for
Alzheimer-type dementia. Currently, there is no proven treatment
for Down's syndrome. Therefore, there is a need to address the
dementia associated with Down's syndrome.
[0209] Genetically programmed degeneration of neurons in certain
areas of the brain cause Huntington's disease. Early symptoms of
Huntington's disease include mood swings, or trouble learning new
things or remembering a fact. Most drugs used to treat the symptoms
of Huntington's disease have side effects such as fatigue,
restlessness, or hyperexcitability. Currently, there is no
treatment to stop or reverse the progression of Huntington's
disease. Therefore, there is a need of a pharmaceutical agent to
address the symptoms with fewer side effects.
[0210] General anxiety disorder (GAD) occurs when a person worries
about things such as family, health, or work when there is no
reason to worry and is unable not to worry. About 3 to 4% of the
U.S. population has GAD during the course of a year. GAD most often
strikes people in childhood or adolescence, but can begin in
adulthood, too. It affects women more often than men. Currently,
treatment involves cognitive-behavioral therapy, relaxation
techniques, and biofeedback to control muscle tension and
medications such as benzodiazepines, imipramine, and buspirone.
These drugs are effective but all have side-effect liabilities.
Therefore, there is a need of a pharmaceutical agent to address the
symptoms with fewer side effects.
[0211] Dementia with Lewy Bodies is a neurodegenerative disorder
involving abnormal structures known as Lewy bodies found in certain
areas of the brain. Symptoms of dementia with Lewy bodies include,
but are not limited to, fluctuating cognitive impairment with
episodic delirium. Currently, treatment concerns addressing the
parkinsonian and psychiatric symptoms. However, medicine to control
tremors or loss of muscle movement may actually accentuate the
underlying disease of dementia with Lewy bodies. Therefore, there
is a need of a pharmaceutical agent to treat dementia with Lewy
bodies.
[0212] Age-related macular degeneration (AMD) is a common eye
disease of the macula which is a tiny area in the retina that helps
produce sharp, central vision required for "straight ahead"
activities that include reading and driving. Persons with AMD lose
their clear, central vision. AMD takes two forms: wet and dry. In
dry AMD, there is a slow breakdown of light-sensing cells in the
macula. There currently is no cure for dry AMD. In wet AMD, new,
fragile blood vessels growing beneath the macula as dry AMD worsens
and these vessels often leak blood and fluid to cause rapid damage
to the macula quickly leading to the loss of central vision. Laser
surgery can treat some cases of wet AMD. Therefore, there is a need
of a pharmaceutical agent to address AMD.
[0213] Parkinson's disease is a neurological disorder characterized
by tremor, hypokinesia, and muscular rigidity. Currently, there is
no treatment to stop the progression of the disease. Therefore,
there is a need of a pharmaceutical agent to address
Parkinson's.
[0214] Tardive dyskinesia is associated with the use of
conventional antipsychotic drugs. This disease is characterized by
involuntary movements most often manifested by puckering of the
lips and tongue and/or writhing of the arms or legs. The incidence
of tardive dyskinesia is about 5% per year of drug exposure among
patients taking conventional antipsychotic drugs. In about 2% of
persons with the disease, tardive dyskinesia is severely
disfiguring. Currently, there is no generalized treatment for
tardive dyskinesia. Furthermore, the removal of the effect-causing
drugs is not always an option due to underlying problems.
Therefore, there is a need for a pharmaceutical agent to address
the symptoms of tardive dyskinesia.
[0215] Pick's disease results from a slowly progressive
deterioration of social skills and changes in personality with the
resulting symptoms being impairment of intellect, memory, and
language. Common symptoms include memory loss, lack of spontaneity,
difficulty in thinking or concentrating, and speech disturbances.
Currently, there is no specific treatment or cure for Pick's
disease but some symptoms can be treated with cholinergic and
serotonin-boosting antidepressants. In addition, antipsychotic
medications may alleviate symptoms in FTD patients who are
experiencing delusions or hallucinations. Therefore, there is a
need for a pharmaceutical agent to treat the progressive
deterioration of social skills and changes in personality and to
address the symptoms with fewer side effects.
[0216] Post-traumatic stress disorder (PTSD) is a form of anxiety
triggered by memories of a traumatic event that directly affected
the patient or that the patient may have witnessed. The disorder
commonly affects survivors of traumatic events including sexual
assault, physical assault, war, torture, natural disasters, an
automobile accident, an airplane crash, a hostage situation, or a
death camp. The affliction also can affect rescue workers at an
airplane crash or a mass shooting, someone who witnessed a tragic
accident or someone who has unexpectedly lost a loved one.
Treatment for PTSD includes cognitive-behavioral therapy, group
psychotherapy, and medications such as Clonazepam, Lorazepam and
selective serotonin-reuptake inhibitors such as Fluoxetine,
Sertraline, Paroxetine, Citalopram and Fluvoxamine. These
medications help control anxiety as well as depression. Various
forms of exposure therapy (such as systemic desensitization and
imaginal flooding) have all been used with PTSD patients. Exposure
treatment for PTSD involves repeated reliving of the trauma, under
controlled conditions, with the aim of facilitating the processing
of the trauma. Therefore, there is a need for better pharmaceutical
agents to treat Post traumatic stress disorder.
[0217] Dysregulation of food intake associated with eating disease,
including bulemia nervosa and anorexia nervosa, involve
neurophysiological pathways. Anorexia nervosa is hard to treat due
to patients not entering or remaining in after entering programs.
Currently, there is no effective treatment for persons suffering
from severe anorexia nervosa. Cognitive behavioral therapy has
helped patients suffering from bulemia nervosa; however, the
response rate is only about 50% and current treatment does not
adequately address emotional regulation. Therefore, there is a need
for pharmaceutical agents to address neurophysiological problems
underlying diseases of dysregulation of food intake.
[0218] Cigarette smoking has been recognized as a major public
health problem for a long time. However, in spite of the public
awareness of health hazard, the smoking habit remains
extraordinarily persistent and difficult to break. There are many
treatment methods available, and yet people continue to smoke.
Administration of nicotine transdermally, or in a chewing gum base
is common treatments. However, nicotine has a large number of
actions in the body, and thus can have many side effects. It is
clear that there is both a need and a demand of long standing for a
convenient and relatively easy method for aiding smokers in
reducing or eliminating cigarette consumption. A drug that could
selectively stimulate only certain of the nicotinic receptors would
be useful in smoke cessation programs.
[0219] Smoke cessation programs may involve oral dosing of the drug
of choice. The drug may be in the form of tablets. However, it is
preferred to administer the daily dose over the waking hours, by
administration of a series of incremental doses during the day. The
preferred method of such administration is a slowly dissolving
lozenge, troche, or chewing gum, in which the drug is dispersed.
Another drug in treating nicotine addiction is Zyban. This is not a
nicotine replacement, as are the gum and patch. Rather, this works
on other areas of the brain, and its effectiveness is to help
control nicotine craving or thoughts about cigarette use in people
trying to quit. Zyban is not very effective and effective drugs are
needed to assist smokers in their desire to stop smoking. These
drugs may be administered transdermally through the use of skin
patches. In certain cases, the drugs may be administered by
subcutaneous injection, especially if sustained release
formulations are used.
[0220] Drug use and dependence is a complex phenomenon, which
cannot be encapsulated within a single definition. Different drugs
have different effects, and therefore different types of
dependence. Drug dependence has two basic causes, that is,
tolerance and physical dependence. Tolerance exists when the user
must take progressively larger doses to produce the effect
originally achieved with smaller doses. Physical dependence exists
when the user has developed a state of physiologic adaptation to a
drug, and there is a withdrawal (abstinence) syndrome when the drug
is no longer taken. A withdrawal syndrome can occur either when the
drug is discontinued or when an antagonist displaces the drug from
its binding site on cell receptors, thereby counteracting its
effect. Drug dependence does not always require physical
dependence.
[0221] In addition drug dependence often involves psychological
dependence, that is, a feeling of pleasure or satisfaction when
taking the drug. These feelings lead the user to repeat the drug
experience or to avoid the displeasure of being deprived of the
drug. Drugs that produce strong physical dependence, such as
nicotine, heroin and alcohol are often abused, and the pattern of
dependence is difficult to break. Drugs that produce dependence act
on the CNS and generally reduce anxiety and tension; produce
elation, euphoria, or other pleasurable mood changes; provide the
user feelings of increased mental and physical ability; or alter
sensory perception in some pleasurable manner. Among the drugs that
are commonly abused are ethyl alcohol, opioids, anxiolytics,
hypnotics, cannabis (marijuana), cocaine, amphetamines, and
hallucinogens. The current treatment for drug-addicted people often
involves a combination of behavioral therapies and medications.
Medications, such as methadone or LAAM
(levo-alpha-acetyl-methadol), are effective in suppressing the
withdrawal symptoms and drug craving associated with narcotic
addiction, thus reducing illicit drug use and improving the chances
of the individual remaining in treatment. The primary medically
assisted withdrawal method for narcotic addiction is to switch the
patient to a comparable drug that produces milder withdrawal
symptoms, and then gradually taper off the substitute medication.
The medication used most often is methadone, taken orally once a
day. Patients are started on the lowest dose that prevents the more
severe signs of withdrawal and then the dose is gradually reduced.
Substitutes can be used also for withdrawal from sedatives.
Patients can be switched to long-acting sedatives, such as diazepam
or phenobarbital, which are then gradually reduced.
[0222] Gilles de la Tourette's Syndrome is an inherited
neurological disorder. The disorder is characterized by
uncontrollable vocal sounds called tics and involuntary movements.
The symptoms generally manifest in an individual before the person
is 18 years of age. The movement disorder may begin with simple
tics that progress to multiple complex tics, including respiratory
and vocal ones. Vocal tics may begin as grunting or barking noises
and evolve into compulsive utterances. Coprolalia (involuntary
scatologic utterances) occurs in 50% of patients. Severe tics and
coprolalia may be physically and socially disabling. Tics tend to
be more complex than myoclonus, but less flowing than choreic
movements, from which they must be differentiated. The patient may
voluntarily suppress them for seconds or minutes.
[0223] Currently simple tics are often treated with
benzodiazepines. For simple and complex tics, Clonidine may be
used. Long-term use of Clonidine does not cause tardive dyskinesia;
its limiting adverse effect is hypotension. In more severe cases,
antipsychotics, such as Haloperidol may be required, but side
effects of dysphoria, parkinsonism, akathisia, and tardive
dyskinesia may limit use of such antipsychotics. There is a need
for safe and effective methods for treating this syndrome.
[0224] Glaucoma is within a group of diseases occurs from an
increase in intraocular pressure causing pathological changes in
the optical disk and negatively affects the field of vision.
Medicaments to treat glaucoma either decrease the amount of fluid
entering the eye or increase drainage of fluids from the eye in
order to decrease intraocular pressure. However, current drugs have
drawbacks such as not working over time or causing side effects so
the eye-care professional has to either prescribe other drugs or
modify the prescription of the drug being used. There is a need for
safe and effective methods for treating problems manifesting into
glaucoma.
[0225] Ischemic periods in glaucoma cause release of excitotoxic
amino acids and stimulate inducible form of nitric oxide synthase
(iNOS) leading to neurodegeneration. Alpha 7 nicotinic agonists may
stimulate the release of inhibitory amino acids such as GABA which
will dampen hyperexcitablity. Alpha 7 nicotinic agonists are also
directly neuroprotective on neuronal cell bodies. Thus alpha 7
nicotinic agonists have the potential to be neuroprotective in
glaucoma.
[0226] Persons afflicted with pain often have what is referred to
as the "terrible triad" of suffering from the pain, resulting in
sleeplessness and sadness, all of which are hard on the afflicted
individual and that individual's family. Pain can manifest itself
in various forms, including, but not limited to, headaches of all
severity, back pain, neurogenic, and pain from other ailments such
as arthritis and cancer from its existence or from therapy to
irradicate it. Pain can be either chronic (persistent pain for
months or years) or acute (short-lived, immediate pain to inform
the person of possible injury and need of treatment). Persons
suffering from pain respond differently to individual therapies
with varying degrees of success. There is a need for safe and
effective methods for treating pain.
[0227] Finally, the compounds of the present invention may be used
in combination therapy with typical and atypical anti-psychotic
drugs. All compounds within the present invention are useful for
and may also be used in combination with each other to prepare
pharmaceutical compositions. Such combination therapy lowers the
effective dose of the anti-psychotic drug and thereby reduces the
side effects of the anti-psychotic drugs. Some typical
anti-psychotic drugs that may be used in the practice of the
invention include Haldol. Some atypical anti-psychotic drugs
include Ziprasidone, Olanzapine, Resperidone, and Quetiapine.
[0228] Compounds of Formula I can be prepared as shown in Scheme 1.
The key step in the preparation of this class of compounds is the
coupling of commercially-available 3-aminoquinuclidine with the
requisite acid chloride (Lv.dbd.Cl), mixed anhydride (e.g.,
Lv=diphenyl phosphoryl, Bis(2-oxo-3-oxazolidinyl)phosphinyl, or
acyloxy of the general formula of O--C(O)--R.sub.Lv, where R.sub.Lv
includes phenyl or t-butyl), or carboxylic acid (Lv.dbd.OH) in the
presence of an activating agent. Suitable activating reagents are
well known in the art, for examples see Kiso, Y., Yajima, H.
"Peptides" pp. 39-91, San Diego, Calif., Academic Press, (1995),
and include, but are not limited to, agents such as carbodiimides,
phosphonium and uronium salts (such as HATU). 19
[0229] Preferably, the acid is coupled with the amino-quinuclidine
using HATU in the presence of DIEA using CH.sub.2Cl.sub.2 as the
solvent.
[0230] It will be apparent to those skilled in the art that the
requisite carboxylic acids can be obtained through synthesis via
literature procedures or through the slight modification
thereof.
[0231] One of ordinary skill in the art will recognize that the
methods described for the reaction of the unsubstituted
3-aminoquinuclidine (R.sub.2.dbd.H) are equally applicable to
substituted compounds (R.sub.2.noteq.H). Such compounds can be
prepared by reduction of the oxime of the corresponding
3-quinuclidinone (see J. Labelled Compds. Radiopharm., 53-60 (1995)
and J. Med. Chem. 988-995, (1998)). The oximes can be prepared by
treatment of the 3-quinuclidinones with hydroxylamine hydrochloride
in the presence of a base. The 3-quinuclidinones, where
R.sub.2=substituted alkyl, or cycloalkyl can be prepared by known
procedures (see Tet. Lett. 1015-1018, (1972), J. Am. Chem. Soc.
1278-1291 (1994), J. Am. Chem. Soc. 4548-4552 (1989), Tetrahedron,
1139-1146 (2000)). The 3-quinuclidinones, where R.sub.2=aryl, can
be prepared by palladium catalyzed arylation as described in J. Am.
Chem. Soc. 1473-1478 (1999) and J. Am. Chem. Soc. 1360-1370
(2000).
[0232] There are a variety of methods for constructing thioamides.
One can treat the corresponding amide with a reagent such as
Lawesson's reagent
(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide).
See Lawesson et. al. in Bull. Soc. Chim. Belg., 229 (1978)), or
P.sub.4S.sub.10 (see Chem. Rev., 45 (1961). Alternatively one can
react a dithiocarboxylic ester with the corresponding quinuclidine
to form the same thioamide.
[0233] The following examples are provided as examples and are not
intended to limit the scope of this invention to only those
provided examples and named compounds. Also, the salts made in the
examples are only exemplary and are not intended to limit the
invention. Any pharmaceutically acceptable salt can be made by one
of ordinary skill in the art. Further, the naming of specific
stereoisomers is for exemplification, and is not intended to limit
in anyway the scope of the invention. The examples were made using
3R-aminoquinuclidine. However, compounds could be made using the
3S-aminoquinuclinde making non-critical changes to the methods
discussed herein. The invention includes the following examples in
pure stereoisomeric form or as racemic mixtures.
EXAMPLE 1
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-6-carboxamide.fumarat-
e
[0234] 20
[0235] Method A. Preparation of 1,3-benzoxazole-6-carboxylic acid
(Acid C1).
[0236] A mixture of 4-amino-3-hydroxybenzoic acid (250 mg, 1.63
mmol) and trimethyl orthoformate (500 .mu.L, 4.57 mmol) is heated
in an oil bath at 100.degree. C. for 2 h. The mixture is cooled to
rt and diluted with MeOH. The resulting solution is filtered
through a pad of Celite, and the filtrate is concentrated in vacuo
to give Acid C1as a brown solid (237 mg, 89%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 13.2, 8.9, 8.3, 8.0, 7.9.
[0237] Method B. Preparation of
N-(I-azabicyclo[2.2.2]oct-3-yl)-1,3-benzox-
azole-6-carboxamide.fumarate.
[0238] To a stirred solution of Acid C1(194 mg, 1.19 mmol) in
anhydrous THF/DMF (5:1, 12 mL) are added DIEA (600 .mu.L, 3.44
mmol) and 3-(R)-aminoquinuclidine dihydrochloride (225mg, 1.13
mmol). The mixture is cooled to -10.degree. C. and HATU (430 mg,
1.13 mmol) is added in one portion. The reaction mixture is allowed
to warm to rt and stirred overnight. The solvents are removed in
vacuo and the residue is partitioned between saturated aqueous
potassium carbonate solution and 95:5 CHCl.sub.3-MeOH. The aqueous
layer is extracted with 95:5 CHCl.sub.3-MeOH (2.times.), and the
combined organic layers are washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. The crude
product is purified by flash chromatography on silica gel. Elution
with CHCl.sub.3-MeOH-ammonium hydroxide (90:9:1) gives an orange
solid. The solid is dissolved in acetone (5 mL) and a hot solution
of fumaric acid (66 mg, 0.58 mmol) in isopropyl alcohol (2 mL) is
added. The mixture is stirred for 30 min in a 50.degree. C. water
bath. The solvents are removed in vacuo and the remaining residue
is dissolved in acetone (5 mL). The mixture is stirred overnight at
rt. The solid precipitate is collected by filtration and washed
with acetone. The solid is dried in vacuo overnight to give 150 mg
(35%) of the title compound as a light yellow solid: .sup.1H NMR
(CD.sub.3OD) .delta. 8.6, 8.2, 8.0, 7.9, 6.7, 4.9, 4.5-4.4,
3.9-3.8, 3.5-3.3, 2.4, 2.3-2.2, 2.1, 2.0-1.9.
EXAMPLE 2
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-6-carboxamide-
.fumarate
[0239] 21
[0240] Preparation of 2-methyl-1,3-benzoxazole-6-carboxylic acid
(Acid C2):
[0241] A mixture of 4-amino-3-hydroxybenzoic acid (500 mg, 3.7
mmol) and trimethyl orthoacetate (1.0 mL, 7.9 mmol) is heated in an
oil bath to 100.degree. C. for 2 h. The mixture is cooled to rt and
diluted with MeOH. The resulting solution is filtered through a pad
of Celite, and the filtrate is concentrated in vacuo to give Acid
C2 as an off-white solid (266 mg, 46%): .sup.1H NMR (DMSO-d.sub.6)
.delta. 13.1, 8.2, 8.0, 7.7, 2.7.
[0242] Coupling:
[0243] Example 2 is obtained using Acid C2 according to Method B
making non-critical changes. .sup.1H NMR (CD.sub.3OD) .delta. 8.1,
7.9,7.7, 6.7,4.9, 4.5-4.4, 3.9-3.8, 3.5-3.3, 2.4-2.3, 2.3-2.2,
2.1-2.0, 2.0-1.9.
EXAMPLE 3
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzoxazole-5-carboxamide.fumarate
[0244] 22
[0245] Preparation of 1,3-benzoxazole-5-carboxylic acid (Acid
C3):
[0246] A mixture of 4-amino-3-hydroxybenzoic acid (1.0 g, 6.5 mmol)
and trimethyl orthoformate (2.0 mL, 18.3 mmol) is heated in an oil
bath at 100.degree. C. for 30 h. The mixture is cooled to rt and
diluted with MeOH. The resulting solution is filtered through a pad
of Celite, and the filtrate is concentrated in vacuo to give Acid
C3 as a brown solid (290 mg, 27%): .sup.1H NMR (DMSO-d.sub.6)
.delta. 13.0, 8.9, 8.3, 8.1, 7.9.
[0247] Coupling:
[0248] Example 3 is obtained using Acid C3 according to Method B
making non-critical changes. .sup.1H NMR (CD.sub.3OD) .delta. 8.6,
8.3, 8.0, 7.8, 6.7, 4.5, 3.9-3.8, 3.5-3.3, 2.4, 2.3-2.2, 2.1-2.0,
2.0-1.9.
EXAMPLE 4
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-1,3-benzoxazole-5-carboxamide-
.fumarate
[0249] 23
[0250] Preparation of 2-methyl-1,3-benzoxazole-5-carboxylic acid
(Acid C4):
[0251] A mixture of 4-amino-3-hydroxybenzoic acid (480 mg, 3.1
mmol) and trimethyl orthoacetate (1.0 mL, 7.9 mmol) is heated in an
oil bath to 107.degree. C. for 2 h. The mixture is cooled to rt and
diluted with MeOH. The resulting solution is filtered through a pad
of silica gel and the filtrate is concentrated in vacuo to give
Acid C4 as an orange solid (490 mg, 88%): .sup.1H NMR
(DMSO-d.sub.6) .delta. 13.0, 8.2, 8.0, 7.8, 2.7.
[0252] Coupling:
[0253] Example 4 is obtained using Acid C4 according to Method B
making non-critical changes. .sup.1H NMR (CD.sub.3OD) .delta. 8.2,
7.9, 7.7, 6.7, 4.9, 4.5-4.4, 3.9-3.8, 3.4-3.3, 2.7, 2.4, 2.3-2.2,
2.1, 2.0-1.9.
EXAMPLE 5
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzothiazole-6-carboxamide.fumara-
te
[0254] 24
[0255] To a stirred solution of 1,3-benzothiazole-6-carboxylic acid
(500 mg, 2.8 mmol) and 3-(R)-aminoquinuclidine dihydrochloride (530
mg, 2.7 mmol) in DMF (27 mL) is added DIEA (1.5 mL, 8.4 mmol). The
solution is stirred for 10 min, followed by cooling with an ice
bath. HATU (1.0 g, 2.7 mmol) is added and the mixture is allowed to
warm to rt and stir 16 h. The solvent is removed in vacuo and the
remaining residue is partitioned between saturated aqueous
potassium carbonate solution and 9:1 CHCl.sub.3-MeOH. The aqueous
layer is extracted with 9:1 CHCl.sub.3-MeOH, and the combined
organic layers are washed with brine, dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo to a clear
residue. The residue is taken up in acetone (3.0 mL) and a hot
solution of fumaric acid (320 mg, 2.8 mmol) in isopropyl alcohol is
added. The mixture is warmed in a water bath at 45.degree. C. for
15 min, and then the reaction is concentrated in vacuo. The residue
is triturated in acetone (3.0 mL) to afford Example 5 as a white
solid (850 mg, 79%): .sup.1H NMR (CD.sub.3OD) .delta. 9.4, 8.6,
8.2, 8.1, 6.7, 4.5, 3.9, 3.5-3.3, 2.4, 2.3, 2.1, 2.0.
EXAMPLE 6
N-((3R)1-azabicyclo[2.2.2]oct-3-yl)indane-5-carboxamide.fumarate
[0256] 25
[0257] Preparation of 5-indancarboxylic acid (Acid 6).
[0258] To a stirred 6% aqueous sodium hypochlorite solution in an
oil bath to 55.degree. C. is added 1-indane-5-yl-ethanone (1.0 g,
6.2 mmol). The solution is stirred at 55.degree. C. for 2 h,
followed by cooling to rt. Solid sodium bisulfite is added until
the solution became clear. The mixture is diluted with water,
followed by aqueous hydrochloric acid (6.0 M). The solid that forms
is filtered and washed several times with water. The solid is dried
under high vacuum at 60.degree. C. for 5 h to afford Acid C6 as a
white solid (0.96 g, 95%): .sup.1H NMR (CDCl.sub.3) .delta. 8.0,
7.9, 7.3, 3.0, 2.1.
[0259] Method C: Coupling.
[0260] To a stirred solution of Acid C6 (500 mg, 3.1 mmol) in dry
DMF (30 mL) is added DIEA (1.6 mL, 9.3 mmol), followed by
3-(R)-aminoquinuclidine dihydrochloride (580 mg, 2.9 mmol). The
solution is cooled with an ice bath before 1.0 g (2.9 mmol) of HATU
is added. The solution is allowed to warm to rt and stir for 16 h.
The solvent is removed in vacuo, and the remaining residue is
partitioned between saturated aqueous potassium carbonate solution
and 9:1 CHCl.sub.3-MeOH. The aqueous layer is extracted with 9:1
CHCl.sub.3-MeOH, and the combined organic layers are washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo to a clear oil. The oil is dissolved in
acetone (2.0 mL) and a hot solution of fumaric acid (320 mg, 2.8
mmol) in isopropyl alcohol (2.0 mL) is added. The solution is
heated in a 45.degree. C. water bath for 15 minutes, followed by
removal of the solvents in vacuo. The remaining solid is triturated
with acetone to afford Example 6 as a white solid (510 mg, 45%):
.sup.1H NMR (CD.sub.3OD) .delta. 7.7, 7.6, 7.3, 6.7, 4.4, 3.8,
3.5-3.2, 3.0, 2.3-2.0, 1.9.
EXAMPLE 7
N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1,3-benzodioxole-5-carboxamide,
4-methylbenzenesulfonate
[0261] 26
[0262] To a stirred suspension of 1,3-benzodioxole-5-carboxylic
acid (380 mg, 2.3 mmol) in dry CH.sub.2Cl.sub.2 (5.0 mL) is added
TEA (320 .mu.L, 2.3 mmol), followed by diphenylphosphoryl azide
(405 .mu.L, 2.0 mmol). In a separate flask, to a stirred suspension
of 3-(R)-aminoquinuclidine dihydrochloride (300 mg, 1.5 mmol) in
CH.sub.2Cl.sub.2 (5.0 mL) is added TEA (530 .mu.L, 3.8 mmol). After
10 min, the aminoquinuclidine solution is rapidly added to the
benzodioxole solution. DMF (1.0 mL) is added, and the combined
mixture is stirred for 24 h at rt. The reaction mixture is
partitioned between saturated aqueous potassium carbonate solution
and CH.sub.2Cl.sub.2. The aqueous layer is extracted with
CH.sub.2Cl.sub.2, and the combined organic layers are washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated in vacuo to a clear residue. The crude product is
purified by flash chromatography on silica gel. Elution with
CHCl.sub.3-MeOH-ammonium hydroxide (90:9:1) gives 130 mg (31%) of a
white foam. The foam (125 mg, 0.46 mmol) is dissolved in EtOAc (1.0
mL) and a solution of p-toluenesulfonic acid monohydrate (90 mg,
0.48 mmol) in MeOH (0.5 mL) is added. The solution is allowed to
stand overnight. The solid that forms is filtered and dried in
vacuo at 50 OC for 48 h to afford the title compound (160 mg, 76%):
.sup.1H NMR (CD.sub.3OD) .delta. 7.7, 7.5, 7.4, 7.3, 6.9, 6.1, 4.4,
3.8, 3.5-3.2, 2.4, 2.3, 2.2, 2.1, 1.9.
EXAMPLE 8
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl][1,3]oxazolo[5,4-c]pyridine-6-carboxam-
ide
[0263] 27
[0264] Preparation of the Acid:
[0265] 2--Chloro-3-pyridinol (20.0 g, 0.154 mole), NaHCO.sub.3
(19.5g, 0.232 mole, 1.5 equ), and 150 mL of water are placed in a
flask. The flask is placed in an oil bath at 90.degree. C., and
after 5 minutes, 37% aqueous formaldehyde (40.5 mL, 0.541 mole, 3.5
equ) is added in six unequal doses in the following order: 12 mL,
3.times.8 mL, then 2.2 mL all at 90-minute intervals and then the
final 2.3 mL after the reaction had stirred for 15 h at 90.degree.
C. The reaction is stirred at 90.degree. C. for another 4 h and
then is cooled by placing the flask in an ice bath. The pH of the
reaction is then adjusted to 1 using 6N HCl. The reaction is
stirred for 1.5 h in an ice bath allowing an undesired solid to
form. The undesired solid is removed by filtration, and the
filtrate is extracted seven times with EtOAc. The combined organic
extracts are concentrated in vacuo, toluene is added to the flask
and removed in vacuo to azeotrope water, and then CH.sub.2Cl.sub.2
is added and removed in vacuo to obtain
2-chloro-6-(hydroxymethyl)-3-pyridinol (C10) as a pale yellow solid
(81% yield) sufficiently pure for subsequent reaction. MS (EI) for
C.sub.6H.sub.6ClNO.sub.2, m/z: 159(M).sup.+.
[0266] 2--Chloro-6-(hydroxymethyl)-3-pyridinol (C10) (11.6 g, 72.7
mmol) and NaHCO.sub.3 (18.3 g, 218 mmol) are added to 200 mL water.
The mixture is stirred until homogeneous, the flask is placed in an
ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is
stirred over the weekend at rt. The pH of the mixture is adjusted
to 3 with 2N NaHSO.sub.4, and the mixture is extracted with
4.times.50 mL EtOAc. The combined organic layer is dried over
anhydrous MgSO.sub.4, is filtered. and the filtrate is concentrated
in vacuo to a yellow solid. The crude solid is washed with EtOAc to
provide 2-chloro-6-(hydroxymethyl)-4-iodo-3- -pyridinol (C12) as an
off-white solid (62% yield), and the filtrate is concentrated to a
small volume and is chromatographed over 250 g silica gel (230-400
mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH.sub.2Cl.sub.2/hexa-
ne/acetic acid. The desire fractions are combined and concentrated
to afford an additional pure C12 (12% yield). MS (El) for
C.sub.6H.sub.5ClNO.sub.2, m/z: 285(M).sup.+.
[0267] 4-(Benzylamino)-2-chloro-6-(hydroxymethyl)-3-pyridinol (C13)
may be produced by amination of
2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C12) with
benzylamine under palladium catalysis. Amination of aryl iodides
with primary amines such as benzylamine under palladium catalysis
is generally described in a review by B. H. Yang and S. L. Buchwald
in J. Organomet. Chem., 576, 125-146, 1999 and in greater detail in
the references therein.
[0268] C13 may be oxidized to
4-(benzylamino)-2-chloro-3-hydroxypyridine-6- -carboxaldehyde (C14)
under a wide variety of conditions (e.g., TPAP and NMO in
CH.sub.2Cl.sub.2). C14 may be oxidized to produce the corresponding
carboxylic acid C15 using an oxidizing reagent such as NaClO.sub.2
and KH.sub.2PO.sub.4 in DMSO/H.sub.2O or Ag.sub.2O, or hydrogen
peroxide or ruthenium tetroxide.
[0269] Removal of the benzyl group and the chloro group of Acid C15
may be accomplished by utilizing hydrogen or a hydrogen source
(e.g., cyclohexene, cyclohexadiene, ammonium formate, hydrazine,
etc.) in the presence of Pd/C or other catalyst, under a variety of
conditions and in various solvents, to produce
4-amino-5-hydroxypyridine-2-carboxylic acid (Acid C16).
[0270] Cyclocondensation of Acid C16 with trimethyl orthoformate in
the presence of catalytic para-toluenesulfonic acid may be
conducted to produce [1,3]oxazolo[5,4-c]pyridine-6-carboxylic acid
(Acid C17).
[0271] Coupling:
[0272] Example 8 is obtained using Acid C17 according to Method B
making non-critical changes. The free base can be made into a
suitable salt.
EXAMPLE 9
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-benzoisothiophene-5-carboxamide
[0273] 28
[0274] Acid C21 can be made by the saponification of the methyl
ester C20, which can be made pursuant to Wynberg, Hans, et al.,
Recl. Trav. Chim. Pays-Bas (1968), 87(10), 1006-1010. Acid C21 can
then be coupled with the amino-quinuclidine using Method B with
non-critical changes to provide Example 9 as the free base that can
be made into a suitable salt.
EXAMPLE 10
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-5-carboxamide.fumar-
ate
[0275] 29
[0276] A solution of sodium sulfideenanohydrate (1.15 g, 4.9 mmol)
in methanol-water (ca. 10 mL, 1:1) is warmed on a hot plate. To
this solution is added elemental sulfur (150 mg, 4.6 mmol). Heating
is continued for 15 min before the solution is poured into a
separate solution of 1.0 g (4.6 mmol) of methyl
4-chloro-3-nitrobenzoate (see: Kuene, J. Am. Chem. Soc. 1962, 48,
837.) in MeOH (5.0 mL). The mixture is stirred for 30 min, followed
by cooling in a refrigerator overnight. The solid precipitate is
filtered, washed with water and methanol, and dried in vacuo at
50.degree. C. to afford 650 mg (65%) of dimethyl
4,4'-dithio-bis-(3-nitrobenzoate) as a yellow solid: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 9.0, 8.2, 7.9, 4.0.
[0277] To a stirred solution of dimethyl
4,4'-dithio-bis-(3-nitrobenzoate) (900 mg, 2.12 mmol) in ethanol is
added tin powder (1.91 g, 17.0 mmol). The mixture is heated in a
70.degree. C. oil bath for 30 minutes before 2.8 mL of concentrated
hydrochloric acid is added drop-wise. After complete addition, the
mixture is stirred for an additional 10 min, followed by cooling to
RT. The reaction mixture is filtered and the fitrate is
concentrated in vacuo to a solid. The solid is washed with 1.0M
aqueous hydrochloric acid and dried in vacuo to afford a yellow
solid. The solid (750 mg, 3.42 mmol) is suspended in formic acid (4
mL) in a 100.degree. C. oil bath. Zinc dust (15 mg) is added to the
reaction. The mixture is stirred for 10 min, followed by cooling to
RT. The mixture is diluted with water and extracted with EtOAc. The
organic layer is dried over MgSO.sub.4, filtered and concentrated
in vacuo to afford 640 mg (97%) of methyl
1,3-benzothiazole-5-carboxylate as a yellow solid: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.1, 8.9, 8.2, 8.1, 4.0.
[0278] To a stirred solution of methyl
1,3-benzothiazole-5-carboxylate (290 mg, 1.5 mmol) in MeOH (20 mL)
is added sodium hydroxide (10 mL of a 5% aqueous solution). The
mixture is heated in a 65.degree. C. oil bath for 30 min, followed
by cooling to RT. The mixture is diluted with water and extracted
with hexanes-ether (1:1). The organic layer is discarded and the
aqueous layer is acidified with concentrated hydrochloric acid to
pH=1. The aqueous layer is extracted with ether. The ethereal layer
is dried over MgSO.sub.4, filtered and concentrated in vacuo to a
yellow powder for 1,3-benzothiazole-5-carboxylic acid (260 mg,
98%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13-12.5, 9.5,
8.6, 8.3, 8.0.
[0279] Example 10 is obtained using 1,3-benzothiazole-5-carboxylic
acid according to the coupling procedure described for making
Example 5 to afford 300 mg (86%) of Example 10 as a white solid.
.sup.1H NMR (MeOH-d.sub.4) .delta. 9.3, 8.6, 8.2, 8.0, 6.7, 4.5,
3.9, 3.5-3.3, 2.4, 2.3, 2.1, 2.0.
EXAMPLE 11
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-6-carbo-
xamide hydrochloride
[0280] 30
[0281] Preparation of
(2S,3R)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine
Dihydrochloride:
[0282] A mixture of 2-methylene-3-quinuclidinone dihydrate
hydrochloride (27.2 g, 0.13 mol, 1 eq) and K.sub.2CO.sub.3 (86.0 g,
0.62 mol, 4.8 eq) is dissolved in 130 mL water and 250 mL
CH.sub.2Cl.sub.2 and stirred vigorously. After 3 days, the layers
are separated and the aqueous layer is extracted with
CH.sub.2Cl.sub.2. The combined organic layers are dried
(MgSO.sub.4), filtered and concentrated to give 17.8g (100%) of
2-methylenequinuclidin-3-one as a yellow oil. MS (ESI) for
C.sub.8H.sub.11NO m/z 138.1 (M.sup.+).
[0283] 2-Methylenequinuclidin-3-one (17.8 g, 0.13 mol, 1 eq) is
dissolved in 40 mL MeOH in a Parr hydrogenation bottle. A THF
slurry of 10% Pd/C (0.57 g) is added. The mixture is hydrogenated
for 45 min at 45 psi, recharging as needed. The mixture is filtered
through a pad of Celite. The Celite is washed with excess MeOH. The
solution is concentrated to give a solid and a yellow oil. The
mixture is taken up in ether, filtered and concentrated to provide
16.2g (90%) of 2-methylquinuclidin-3-one. MS (ESI) for
C.sub.8HR.sub.3NO m/z 140.2 (M.sup.+).
[0284] 2-Methylquinuclidin-3-one (39.6 g, 0.28 mol, 1 eq) and
hydroxylamine hydrochloride (20.0 g, 0.29 mol, 1.01 eq) are
dissolved in 170 mL absolute EtOH. The mixture is heated under
reflux until a clear solution develops (about 20 min), after which
is immediately followed by formation of a white precipitate. The
reaction is cooled and allowed to stand overnight. The mixture is
cooled in an ice bath, the solids are filtered and dried (house
vacuum) to provide 46.4 g of
(3E/Z)-2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime hydrochloride.
A second crop of 2.4 g is also obtained. Overall yield is 48.8 g
(90%). The 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime
hydrochloride is a 4:1 mixture of oxime isomers. MS (ESI) for
C.sub.8H.sub.14N.sub.2O m/z 154.8 (M.sup.+). Partial .sup.1H NMR
(400 MHz, DMSO) .delta. 4.39 (0.2H), 4.29 (0.8H), 1.57 (0.6H), 1.47
(2.4H).
[0285] A solution of sodium n-propoxide (prepared from 5.5 g sodium
(0.24 mol) and 100 mL n-propanol) is added dropwise to a suspension
of (3E/Z)-2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime
hydrochloride (45.8 g, 0.24 mol, 1 eq) in 150 mL n-propanol. After
complete addition, 250 mL of n-propanol is added, and the mixture
is heated under reflux. Sodium (55.2 g, 2.40 mol, 10 eq) is added
in portions to the refluxing mixture. The mixture is heated under
reflux overnight. After about 14 h, the mixture is cooled, water is
added and the layers are separated. The n-propanol layer is washed
with brine and dried (MgSO.sub.4). The combined aqueous layers are
extracted with CHCl.sub.3 and dried (MgSO.sub.4). The combined,
dried organic layers are treated with about 70 mL concentrated HCl.
The solvent is removed in vacuo. Absolute EtOH is added, and the
solvent is removed. The sequence is repeated 2-3 times with fresh
EtOH until a white solid formed. Absolute EtOH is added, the solids
are filtered and dried (vacuum oven, about 60.degree. C.) to
provide 36.5 g of trans 3-amino-2-methylquinuclidine
dihydrochloride. MS (ESI) for C.sub.8H.sub.16N.sub.2 m/z 141.3
(M.sup.+). Additional material is obtained from the mother liquor:
7.8 g (.sub.2nd crop) and 1.5 g (3.sup.rd crop); this material is a
mixture of both trans and cis isomers.
[0286] 4-Chlorobenzoic acid (26.3 g, 0.17 mol, 1.1 eq) and TEA (106
mL, 0.76 mol, 5 eq) are dissolved in 300 mL THF. Diphenylphosphoryl
chloride (32.0 mL, 0.17 mol, 1.1 eq) is added dropwise. After 1 h,
trans 2-methylquinuclidin-3-amine dihydrochloride (32.6 g, 0.15
mol, 1 eq) is added. The mixture is allowed to stir at RT
overnight. 1N NaOH (about 100 mL) is added, and the pH is adjusted
to pH 11 with 50% NaOH and about 50 g K.sub.2CO.sub.3. The layers
are separated. The aqueous layer is extracted with CHCl.sub.3. The
combined organic layers are dried (MgSO.sub.4), filtered and
concentrated. The residue is taken up in heptane and concentrated
to give 35.1 g (82%) of 4-chloro-N-(2-methyl-1-a-
zabicyclo[2.2.2]oct-3-yl)phenyl-2-carboxamide as a light yellow
solid. The enantiomers are separated on a 5.times.50 cm Chiralcel
OD column at 30.degree. C., eluting with 15% IPA/heptane+0.1% DEA
at 90 mL/min to provide 17.4 g of the eutomer at about 97% ee. The
p-TsOH salt is prepared and recrystallized from EtOH/EtOAc.
[.alpha.].sup.25.sub.D=+30(c 0.96, methanol). HRMS (FAB) calcd for
C.sub.15H.sub.19ClN.sub.2O+H 279.1264, found 279.1272.
[0287] A solution of
4-chloro-N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-
-yl]benzamide (17.2g, 61.7mmol) in absolute EtOH (70mL) and
concentrated HCl (70 mL) is heated under reflux for about 64 h. The
reaction is monitored for disappearance of starting amide by
reverse phase HPLC (ZORBAX Eclipse XDB--C8, 4.6 mm.times.15 cm,
80:12:8 H.sub.2O/CH.sub.3CN/IPA). The solvent is removed in vacuo.
The residue is dissolved/suspended in EtOH and the solvent is
removed (twice). The solid is suspended in boiling EtOH, filtered
and dried (vacuum oven, about 60.degree. C.) to provide 8.8 g (67%)
of N-(2S,3R)-2-methyl-1-azabicyclo[- 2.2.2]octan-3-amine
dihydrochloride as a white solid. MS (EI) m/z 141.2 (M.sup.+).
[0288] Coupling:
[0289] 1,3-Benzothiazole-6-carboxylic acid (0.1 8g, 1.0 mmol), HATU
(0.465g, 1.22 mmol) and
(2S,3R)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride
(0.215 g, 1.0 mmol) are suspended in 15 mL CH.sub.3CN. DIEA (1.4
mL, 8.0 mmol) is added dropwise. The reaction is warmed to RT.
After 48 h, the solvent is removed in vacuo. The residue is taken
up in CHCl.sub.3, 1N NaOH is added and the mixture is extracted
with CHCl.sub.3. The combined organic layers are dried
(MgSO.sub.4), filtered and concentrated. The residue is purified by
chromatography (Biotage 40S, 90:9:1 CHCl.sub.3/MeOH/NH.sub.4OH).
The hydrochloride salt is prepared and recrystallized from
MeOH/EtOAc to provide 0.123 g (36%) of the product. HRMS (FAB)
calculated for C.sub.16H.sub.19N.sub.3OS+H 302.1327, found
302.1311.
EXAMPLE 12
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-6-carboxam-
ide
[0290] 31
[0291] 3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved in
concentrated NH.sub.4OH (200 mL) using an overhead stirrer and is
treated slowly dropwise with a solution of iodine (23.4 g, 92 mmol)
and KI (18.26 g, 110 mmol) in water (100 mL). The solution is
stirred for 1 h at rt and then treated rapidly dropwise with
concentrated HCl (180 mL). The white solid is collected via
filtration, rinsed with water and dried overnight [by pulling air
through the solid]in vacuo to afford 13.05 g (54%) of
3-hydroxy-4-iodobenzoic acid as a tan solid. .sup.1H NMR
(DMSO-d.sub.6): .delta. 7.13, 7.43, 7.80, 10.71, 12.98 ppm.
[0292] 3-Hydroxy-4-iodobenzoic acid (12.55 g, 47.5 mmol) is
dissolved in MeOH (200 mL), treated slowly dropwise with thionyl
chloride (32.3 mL, 442.9 mmol) at rt, then heated to reflux for 20
h. The mixture is concentrated to dryness and partitioned between
CH.sub.2Cl.sub.2 (100 mL) and saturated NaHCO.sub.3 (50 mL). Not
all of the residue is solubilized, so the mixture is filtered and
the solid is washed with a small amount of CH.sub.2Cl.sub.2 and
MeOH. The original filtrate and the organic washes are combined,
concentrated to dryness, dissolved in 10% MeOH/CH.sub.2Cl.sub.2
(200 mL), diluted with water (50 mL) and the layers separated. The
organics are washed with saturated NaHCO.sub.3 (2.times.50 mL),
then water (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to a tan solid. This solid is triturated with
CH.sub.2Cl.sub.2 (50 mL) and filtered. The two solids are combined
to afford 9.4 g (70%) of methyl 3-hydroxy-4-iodobenzoate as a beige
solid. HRMS (FAB) calcd for C.sub.8H.sub.7I.sub.3+H.sub.1:
278.9520, found 278.9521.
[0293] Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is
combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol),
bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and
cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl.sub.3 (40 mL)
in a dry flask, under nitrogen. TEA (8.14 mL<58.4 mmol) is added
and the mixture is heated to 50.degree. C. for 4 h. The mixture is
diluted with CHCl.sub.3 (60 mL), washed with 5% HCl (2.times.40
mL), dried over anhydrous MgSO.sub.4 and concentrated to a brown
paste (8.31 g). The crude material is chromatographed over a
standard 90 g Biotage column, eluting with 10% EtOAc/hexane (1 L)
followed by 15% EtOAc/hexane (1 L). The appropriate fractions are
combined and concentrated to afford 4.22 g (91%) of methyl
3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid.
HRMS (FAB) calcd for C.sub.13H.sub.16O.sub.3SI+H.sub.1: 249.0947,
found 249.0947.
[0294] Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (540
mg, 2.17 mmole) is combined with 4 ml formic acid under nitrogen.
The reaction is warmed to 80.degree. C. for 12 h, is cooled to rt,
and the volatiles are removed in vacuo. The black residue is
chromatographed over 25 g silica gel (230-400 mesh) eluting with
15% EtOAc/hexane. The appropriate fractions are combined and
concentrated to provide 350 mg (83%) of methyl
4-acetyl-3-hydroxybenzoate as a pale yellow solid. .sup.1H NMR
(CDCl.sub.3) .delta. 2.70, 3.95, 7.54, 7.64, 7.82, 12.10 ppm.
[0295] Methyl 4-acetyl-3-hydroxybenzoate (350 mg, 1.8 mmole) is
combined with 5 ml absolute EtOH. The solution is treated with
hydroxylamine hydrochloride (125 mg, 1.8 mmole) dissolved in 0.9 ml
2N aqueous NaOH, and the reaction is stirred overnight at rt. The
volatiles are removed in vacuo and the residue is washed with
H.sub.2O, collected, and dried to give 294 mg (78%) of methyl
3-hydroxy-4-[N-hydroxyethanimidoyl]benzoate as a tan solid. MS (El)
m/z: 209 (M.sup.+).
[0296] Methyl 3-hydroxy-4-[N-hydroxyethanimidoyl]benzoate (250 mg,
1.19 mmole) is combined with triphenylphosphine (446 mg, 1.7 mmole)
in 14 ml dry THF in a dry flask under nitrogen. The solution is
treated slowly dropwise with N,N'-diethylazidodicarboxylate (268
.mu.L, 1.7 mmole) in 10 ml dry THF. The reaction is stirred 4 h at
rt. The volatiles are removed in vacuo and the residue is
chromatographed over 30 g silica gel (230-400 mesh) eluting with
10% EtOAc/hexane. The appropriate fractions are combined and
concentrated to provide 125 mg (55%) of methyl
3-methyl-1,2-benzisoxazole-6-carboxylate slightly contaminated
(<10%) with methyl 4-acetyl-3-hydroxybenzoate. .sup.1H NMR
(CDCl.sub.3) .delta. 2.64, 4.00, 7.70, 8.01, 8.25 ppm.
[0297] Methyl 3-methyl-1,2-benzisoxazole-6-carboxylate (170 mg,
0.89 mmole) is dissolved in 6 ml MeOH under nitrogen. The solution
is treated with 2N aqueous NaOH (1 ml, 2 mmole) and the mixture is
stirred 4 h at rt. The volatiles are removed in vacuo and the
residue is dissolved in 4 ml water. The pH of the solution is
adjusted to 3 with 10% aqueous HCl, the white precipitate is
collected, is washed with water, and is dried to give 144 mg (92%)
of 3-methyl-1,2-benzisoxazole-6-carboxylic acid as a white solid.
MS m/z (ESI): 176.2 (M-H).sup.-.
[0298] 3-Methyl-1,2-benzisoxazole-6-carboxylic acid (139 mg, 0.78
mmole) is combined with (3R)-aminoquinuclidine dihydrochloride (156
mg, 0.78 mmole) and DIEA (272 .mu.L, 1.56 mmole) in 3 ml DMF under
nitrogen. The mixture is treated with HATU (296 mg, 0.78 mmole),
and the reaction is stirred overnight at rt. The volatiles are
removed in vacuo and the residue is partitioned between 1.times.10
ml 10% MeOH/CHCl.sub.3 and 1.times.10 ml 1:1 saturated sodium
chloride/ conc. NH.sub.4OH. The aqueous layer is washed with
1.times.10 ml CHCl.sub.3 and the combined organic layer is dried
over K.sub.2CO.sub.3. The dried organic layer is concentrated in
vacuo to give an amber residue. The crude material is
chromatographed over 15 g silica gel (230-400 mesh) eluting with 7%
MeOH/CHCl.sub.3+1% conc. NH.sub.4OH. The appropriate fractions are
combined and concentrated to give a pale foam. The foam is
crystallized from Et.sub.2O to provide 163 mg (72%) of
N-[(3R)-1-azabicyclo[2.2.2]oct--
3-yl]-3-methyl-1,2-benzisoxazole-6-carboxamide as an off-white
solid. MS (EI) m/z: 285 (M.sup.+).
EXAMPLE 13
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1,2-benzisoxazole-5-carboxam-
ide
[0299] 32
[0300] Example 13 is obtained according to the methods discussed
for preparing Example 12 starting with 4-hydroxybenzoic acid to
make 3-methyl-1,2-benzisoxazole-5-carboxylic acid. Example 13 is
obtained in 79% yield for the last step (coupling). MS (EI) m/z:
285 (M.sup.+).
EXAMPLE 14
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-6-carboxamide.fumarate
[0301] 33
[0302] To a stirred solution of 3-amino-4-methylbenzoic acid (5.0
g, 33 mmol) in a mixture of water (50 mL) and concentrated
hydrochloric acid (15 mL) in an acetone-crushed ice bath is added a
solution of sodium nitrite in water (12 mL) dropwise. The solution
is stirred for 10 min, followed by the addition of tert-butyl
mercaptan (1.8 mL, 16 mmol). The mixture is stirred for 1 h. The
solid precipitate is filtered, washed with water and dried in vacuo
to obtain 3.85 g (95%) of
3-[(E)-(tert-butylthio)diazenyl]-4-methylbenzoic acid as a tan
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.2, 7.8, 7.5,
7.3, 2.1, 1.6.
[0303] To a stirred solution of potassium tert-butoxide (8.1 g, 73
mmol) in DMSO (30 mL) was added a solution of
3-[(E)-(tert-butylthio)diazenyl]-- 4-methylbenzoic acid (1.9 g, 7.3
mmol) at RT. The mixture was stirred overnight, followed by the
adition of ice water. The aqueous layer was extracted with ethyl
acetate. The organic layer was dicarded. The pH of the aqueous
layer was adjusted to 4-5 with aqueous 1N HCl. The aqueous layer
was extracted with ethyl acetate. The organic layer was washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to
afford 800 mg (97%) of 1H-indazole-6-carboxylic acid as a tan
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.4, 13.0, 8.2,
8.1, 7.9, 7.7.
[0304] To a stirred solution of I H-indazole-6-carboxylic acid
(160, 1.0 mmol) in anhydrous DMF (10 mL) are added N,N-DIEA (520
.mu.L, 3.0 mmol) and 3-(R)-aminoquinuclidine dihydrochloride (190
mg, 0.95 mmol). The mixture is cooled to 0C., and HATU (360 mg,
0.95 mmol) is added in one portion. The reaction mixture is allowed
to warm to rt and stir overnight. The solvent is removed in vacuo
and the residue is partitioned between saturated aqueous potassium
carbonate solution and chloroform. The aqueous layer is extracted
with chloroform (2.times.). The combined organic layers are washed
with brine, dried over anhydrous sodium sulfate, filtered and
concentrated in vacuo. The crude product is purified by flash
chromatography on silica gel. Elution with
CHCl.sub.3-MeOH-NH.sub.4OH (89:9:1) gives the carboxamide as a
clear solid (220 mg, 87%).
[0305] To a stirred solution of the carboxamide (220 mg, 0.82 mmol)
in MeOH (10 mL) is added a warm solution of fumaric acid (95 mg,
0.82 mmol) in MeOH (10 mL). The mixture is stirred for 10 min at
50.degree. C. The solvent is removed in vacuo and the remaining
residue is diluted with acetone (15 mL) and water (few drops). The
mixture is stirred overnight at rt. The solid is collected by
filtration, washed with acetone, and dried in vacuo overnight to
afford 240 mg (74%) of Example 14 as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.2, 8.1, 7.9, 7.6, 6.7, 4.5, 3.9,
3.5-3.3, 2.4,2.3, 2.1, 1.9.
[0306] The benzothiazole and benzimidazole intermediates can be
prepared using the methods as shown in Scheme 3 or Scheme 4,
respectively. The benzoxazole intermediates can be prepared using
methods described in Campaigne, E.; Van Verth, J. E., J. Org.
Chem., 1958, 23, 1344-1346, whereby the requisite o-aminophenol is
treated with diethyloxalate. An alternate preparation of these
compounds utilizes an approach described in Pol. J. Pharm., 1984,
683-688, wherein the o-aminophenol is treated with glycolic acid.
The resultant alcohol is then oxidized with KMnO.sub.4 to afford
the desired benzoxazole-2-carboxylic acid derivative. Similar
approaches can be followed to afford the desired benzothiazole and
benzimidazole derivatives. 34 35
[0307] Alternatively, for where there is substitution on the
imidazole: 36
[0308] The synthetic route to other compounds of interest is shown
in Scheme 4. Heating C1010 in neat diethyl oxalate provides C1011.
Alternatively, heating C1010 in neat glycolic acid provides an
alcohol which is subsequently oxidized with KMnO.sub.4 to afford
C1012 (Pol. J. Pharm. 1984, 683-688). In yet another approach to
compounds of the present invention, 2-halonitroaryl or heteroaryl
compounds are subjected to amines wherein a well documented
ipso-displacement of the halogen group occurs to provide a
nitro-derivative that can be reduced, using methods well known to
those or ordinary skill in the art, yielding C1016. Finally, using
methods described earlier, C1016 can be transformed into C1013
directly using diethyloxalate or into C1017 using glycolic acid
followed by oxidation of the alcohol to the carboxylic acid.
[0309] The coupling of 3-aminoquinuclidine occurs using either the
carboxylic acids, such as C1012 or C1013, or the ethyl esters, such
as C1001, C1011, or C1017, as shown in Scheme 5. 37
[0310] 2-Carboethoxy derivatives can be directly coupled to
(R)-3-aminoquinuclidine upon heating in the ester in ethanol at
reflux. An alternate route entails subjecting the ester to
hydrolysis providing a carboxylic acid. The carboxylic acid can
then be coupled to (R)-3-aminoquinuclidine using a variety of amide
bond coupling reagents.
EXAMPLE 1001
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carboxamide
hydrochloride
[0311] 38
[0312] Step 1001a: Preparation of Ethyl
2-benzothiazolecarboxylate.
[0313] A solution of 2-aminothiophenol (10.7 mL, 0.1 mol) in
diethyl oxalate (27.3 mL, 0.2 mol) is heated at reflux for 4 hr.
The solution is cooled to rt and poured into a solution consisting
of water (150 mL), conc. HCl (50 mL) and 95% EtOH (70 mL). With
stirring, the oil dissolved and a solid formed. The solution is
cooled in an ice bath, the solid is collected by vacuum filtration
and the solids are washed with a solution consisting of EtOH/water
(25/75) to afford a dark solid. This material is purified by
crystallization from hot (68.degree. C.) ligroin to yield ethyl
2-benzothiazolecarboxylate (7.5 g, 36%). Elemental analysis for
C.sub.10H.sub.9NO.sub.2S: Calc: C, 57.95; H, 4.38; N, 6.76. Found:
C, 57.99; H, 4.28; N, 6.78.
[0314] Step 1001b: Coupling.
[0315] Ethyl 2-benzothiazolecarboxylate (0.918 g, 4.43 mmol) is
dissolved in MeOH (20 mL) and 2 N NaOH (3.0 mL) is added. The
mixture is stirred at rt for 2 hr, then lyophilized to afford the
sodium salt of the 2-benzothiazolecarboxylate. The crude salt is
dissolved in THF (25 mL) and cooled to 0.degree. C. To this is
added 3-(R)-aminoquinuclidine dihydrochloride, DIEA (1.7 g, 2.3 mL,
13 mmol) and HATU (1.71 g, 4.49 mmol). The mixture is stirred at rt
for 6 hr, diluted with CH.sub.2Cl.sub.2 (15 mL) and washed with 1 N
NaOH followed by sat. aq. NaHCO.sub.3. The material is purified by
passage through acidic ion exchange resin. The free base is taken
up in 1 M HCl/MeOH (8 mL) and stirred for 1.5 hr. Isopropanol and
Et.sub.2O are added and the solid is isolated by vacuum filtration
to afford Example 1001 in 25% yield. Elemental analysis for
C.sub.15H.sub.17N.sub.3OS.HCl: Calc: C, 55.63; H, 5.60; N, 12.98.
Found: C, 54.74; H, 5.73; N, 12.69. Theo.: C, 54.87; H, 5.68; N,
12.80.
EXAMPLE 1002
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-fluoro-1,3-benzothiazole-2-carboxam-
ide hydrochloride
[0316] 39
[0317] Step 1002a: Preparation of Ethyl
6-fluoro-1,3-benzothiazole-2-carbo- xylate
[0318] A solution of 5-fluoro-2-aminobenzenethiol (0.94 g, 6.6
mmol) in diethyl oxalate (1.8 mL, 13 mmol) is heated at reflux for
overnight. The solution is poured into a mixture of water (9.8 mL),
conc. HCl (3.3 mL), and EtOH (4.6 mL). The material is extracted
with CHCl.sub.3 (3.times.100 mL). The combined organic extracts are
dried over MgSO.sub.4, filtered and concentrated to yield an oil.
The material is purified by chromatography (25% hexanes/75%
CHCl.sub.3) to afford a solid that is recrystallized from petroleum
ether (0.16 g, 11%). MS for C.sub.10H.sub.8NO2SF: m/z 226
(M+H).sup.+.
[0319] Step 1002b: Coupling.
[0320] 3-(R)-Aminoquinuclidine dihydrochloride (89 mg, 0.68 mmol)
is dissolved in EtOH (10 mL). Ethyl
6-fluoro-1,3-benzothiazole-2-carboxylate (140 mg, 0.62 mmol) is
added and the solution is heated at reflux overnight. MS indicated
starting material remained; therefore, additional 3
(R)-aminoquinuclidine dihydrochloride (90 mg, 0.7 mmol) is added
and the solution is heated for an additional 24 hr. The solution is
concentrated and the material is purified by chromatography (10%
MeOH, 89.5% CHCl.sub.3, 0.5% NH.sub.4OH). The material is
crystallized from 3 M HCl/MeOH to afford Example 1002 (189 mg,
79%). MS C.sub.15H.sub.16N.sub.3- SFO: m/z 306 (M+H).sup.+.
EXAMPLE 1004
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3H-imidazo[4,5-b]pyridine-2-carboxami-
de hydrochloride
[0321] 40
[0322] Step 1004a: Preparation of
3H-imidazo[4,5-b]pyridin-2-ylmethanol.
[0323] 2,3-Diaminopyridine (0.74 g, 6.8 mmol) and glycolic acid
(1.1 g, 15 mmol) are heated at reflux for 4.5 hr. The solution is
cooled to rt, and sat. aq. NaHCO.sub.3 is added until the solution
is basic. The resulting solids are collected by vacuum filtration
and recrystallized from water (34% yield). MS
C.sub.7H.sub.7N.sub.3O: m/z 150.0 (M+H).sup.+.
[0324] Step 1004b: Preparation of
3H-imidazo[4,5-b]pyridine-2-carboxylic acid.
[0325] To a boiling solution of KMnO.sub.4 (0.38 g, 2.4 mmol) in
water (8 mL), a boiling solution of
3H-imidazo[4,5-b]pyridin-2-ylmethanol (0.20 g, 1.4 mmol) and
Na.sub.2CO.sub.3 (0.19 g, 1.5 mmol) in water (6 mL) is added. The
resulting mixture is heated at reflux for 4 hr. The hot mixture is
filtered, the filtrate is cooled to rt, and the pH adjusted to 2
using conc. HCl. The resulting precipitate is collected by vacuum
filtration to afford 3H-imidazo[4,5-b]pyridine-2-carboxylic acid in
100% yield: MS for C.sub.7H.sub.5N.sub.30.sub.2: m/z 164
(M+H).sup.+.
[0326] Step 1004c: Coupling.
[0327] To 3H-imidazo[4,5-b]pyridine-2-carboxylic acid (90 mg, 0.55
mmol) in DMF (4 mL) is added (R)-(+)-3-aminoquinuclidine
dihydrochloride (0.11 g, 0.56 mmol), DIEA (0.25 g, 0.35 mL, 1.9
mmol) and HATU (0.21 g, 0.56 mmol). The mixture is stirred
overnight at rt, diluted with CH.sub.2Cl.sub.2 (50 mL) and washed
with 1 N NaOH (2.times.50 mL) followed by sat. aq. NaHCO.sub.3 (50
mL). The material is purified by passage through acidic ion
exchange resin. The free base is taken up in 3 M HCl/MeOH (10 mL)
and stirred for 1.5 hr. Isopropanol and Et.sub.2O are added and the
solid is isolated by vacuum filtration to afford Example 1004 in
57% yield. MS for C.sub.14H.sub.17N.sub.5O: 272 (M+H).sup.+.
EXAMPLE 1005
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1,3-benzothiazole-2-carbo-
xamide hydrochloride
[0328] 41
[0329] Coupling:
[0330] A MeOH solution of ethyl 1,3-benzothiazole-2-carboxylate
(0.48 g, 2.3 mmol) is added to a solution of NaOH (0.096 g, 2.4
mmol) dissolved in 7 mL MeOH. After 1 h, the solvent is removed.
The solids are washed with ether and dried in vacuo to provide 0.43
g (92%) of the sodium salt. Sodium 1,3-benzothiazole-2-carboxylate
(0.21 g, 1.05 mmol), HATU (0.46 g, 1.2 mmol) and
(2S,3R)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride
(0.22 g, 1.02 mmol) are suspended in 15mL CH.sub.3CN. DIEA (1.5mL,
8.6mmol) is added dropwise. After 24 h, 1N NaOH is added, and the
mixture is extracted with CHCl.sub.3. The combined organic layers
are dried (MgSO.sub.4), filtered and concentrated. The residue is
purified by chromatography (Biotage 40S, 90:9.5:0.5
CHCl.sub.3/MeOH/NH.sub.4OH). The hydrochloride salt is prepared and
recrystallized from MeOH/EtOAc to provide 0.173 g (50%) of the
product. HRMS (FAB) calculated for C.sub.16H.sub.19N.sub.3OS+H
302.1327, found 302.1330.
[0331] Materials and Methods for identifying binding constants:
[0332] Membrane Preparation. Male Sprague-Dawley rats (300-350 g)
are sacrificed by decapitation and the brains (whole brain minus
cerebellum) are dissected quickly, weighed and homogenized in 9
volumes/g wet weight of ice-cold 0.32M sucrose using a rotating
pestle on setting 50 (10 up and down strokes). The homogenate is
centrifuged at 1,000.times.g for 10 minutes at 4.degree. C. The
supernatant is collected and centrifuged at 20,000.times.g for 20
minutes at 4.degree. C. The resulting pellet is resuspended to a
protein concentration of 1-8 mg/mL. Aliquots of 5 mL homogenate are
frozen at -80.degree. C. until needed for the assay. On the day of
the assay, aliquots are thawed at room temperature and diluted with
Kreb's -20 mM Hepes buffer pH 7.0 (at room temperature) containing
4.16 mM NaHCO.sub.3, 0.44 mM KH.sub.2PO.sub.4, 127 mM NaCl, 5.36 mM
KCl, 1.26 mM CaCl.sub.2, and 0.98 mM MgCl.sub.2, so that 25-150
.mu.g protein are added per test tube. Proteins are determined by
the Bradford method (Bradford, M. M., Anal. Biochem., 72, 248-254,
1976) using bovine serum albumin as the standard.
[0333] Binding Assay. For saturation studies, 0.4 mL homogenate are
added to test tubes containing buffer and various concentrations of
radioligand, and are incubated in a final volume of 0.5 mL for 1 hr
at 25.degree. C. Nonspecific binding was determined in tissues
incubated in parallel in the presence of 0.05 ml MLA for a final
concentration of 1 .mu.M MLA, added before the radioligand. In
competition studies, drugs are added in increasing concentrations
to the test tubes before addition of 0.05 ml [.sup.3H]-MLA for a
final concentration of 3.0 to 4.0 nM [.sup.3H]-MLA. The incubations
are terminated by rapid vacuum filtration through Whatman GF/B
glass filter paper mounted on a 48 well Brandel cell harvester.
Filters are pre-soaked in 50 mM Tris HCl pH 7.0-0.05%
polyethylenimine. The filters are rapidly washed two times with 5
mL aliquots of cold 0.9% saline and then counted for radioactivity
by liquid scintillation spectrometry.
[0334] Data Analysis. In competition binding studies, the
inhibition constant (Ki) was calculated from the concentration
dependent inhibition of [.sup.3H]-MLA binding obtained from
non-linear regression fitting program according to the
Cheng-Prusoff equation (Cheng, Y. C. and Prussoff, W. H., Biochem.
Pharmacol., 22, pp. 3099-3108, 1973). Hill coefficients were
obtained using non-linear regression (GraphPad Prism sigmoidal
dose-response with variable slope).
[0335] The aforementioned examples have the provided Ki values:
1 Example # Ki (nM) Example # Ki (nM) Example 3 32 Example 7 24
Example 4 305 Example 11 92 Example 5 30 Example 1005 73 Example 6
110
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