U.S. patent application number 10/868637 was filed with the patent office on 2004-11-11 for azabicyclic compounds for the treatment of disease.
Invention is credited to Acker, Brad A., Groppi, Vincent E. JR., Jacobsen, Eric Jon, Piotrowski, David W., Walker, Daniel Patrick.
Application Number | 20040224976 10/868637 |
Document ID | / |
Family ID | 27757678 |
Filed Date | 2004-11-11 |
United States Patent
Application |
20040224976 |
Kind Code |
A1 |
Walker, Daniel Patrick ; et
al. |
November 11, 2004 |
Azabicyclic compounds for the treatment of disease
Abstract
The invention provides compounds of Formula I: 1 wherein
Azabicyclo 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 in pharmaceuticals in
which .alpha.7 is known to be involved.
Inventors: |
Walker, Daniel Patrick;
(Noank, CT) ; Piotrowski, David W.; (Groton Long
Pointe, CT) ; Jacobsen, Eric Jon; (Chesterfield,
MO) ; Acker, Brad A.; (Chesterfield, MO) ;
Groppi, Vincent E. JR.; (Kalamazoo, MI) |
Correspondence
Address: |
PHARMACIA & UPJOHN
301 HENRIETTA ST
0228-32-LAW
KALAMAZOO
MI
49007
US
|
Family ID: |
27757678 |
Appl. No.: |
10/868637 |
Filed: |
June 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10868637 |
Jun 15, 2004 |
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10366431 |
Feb 13, 2003 |
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60357926 |
Feb 19, 2002 |
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Current U.S.
Class: |
514/304 ;
514/412; 546/124; 548/453 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 25/16 20180101; A61P 27/02 20180101; A61P 3/04 20180101; A61P
25/30 20180101; A61P 27/06 20180101; A61P 21/04 20180101; A61P
25/22 20180101; A61P 25/00 20180101; A61P 25/04 20180101; A61P
43/00 20180101; A61P 25/14 20180101; A61P 25/24 20180101; A61P
25/18 20180101; C07D 487/08 20130101; A61P 25/02 20180101; C07D
471/08 20130101 |
Class at
Publication: |
514/304 ;
514/412; 546/124; 548/453 |
International
Class: |
C07D 451/02; C07D
487/02 |
Claims
1. A method for treating a disease or condition in a mammal in need
thereof, wherein the mammal would receive symptomatic relief from
the administration of an .alpha.7 nicotinic acetylcholine receptor
agonist comprising administering to the mammal a therapeutically
effective amount of a compound according to Formula I: 74wherein
Azabicyclo is 75R.sub.1 is H, alkyl, halogenated alkyl, cycloalkyl,
substituted phenyl, or substituted naphthyl; R.sub.2 is H, F, Cl,
Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or
aryl; k is 1 or 2, provided that when k is 2, each R.sub.2 is other
than H; R.sub.3 is H, lower alkyl, lower substituted alkyl, or
lower halogenated alkyl; W.sup.1 is O, S, or N(R.sub.15); W.sup.5
and W.sup.6 are independently H or a bond to the carbonyl of
Formula I, provided that only one of W.sup.5 and W.sup.6 is said
bond and the other is H; Each R.sub.4 is independently H, F, Cl,
Br, I, alkyl, halogenated alkyl, substituted alkyl, alkenyl,
halogenated alkenyl, substituted alkenyl, alkynyl, halogenated
alkynyl, substituted alkynyl, cycloalkyl, halogenated cycloalkyl,
substituted cycloalkyl, heterocycloalkyl, halogenated
heterocyloalkyl, substituted heterocycloalkyl, lactam
heterocylcoalkyl, phenyl, substituted phenyl, --OR.sub.10,
--SR.sub.10, --SOR.sub.10, --SO.sub.2R.sub.10,
--NR.sub.10C(O)R.sub.5, --NR.sub.10C(O)R.sub.6,
--NR.sub.10C(O)R.sub.8, --N(R.sub.10).sub.2, --NO.sub.2,
--C(O)R.sub.10, --CN, --C(O).sub.2R.sub.10, --C(O)NHR.sub.10,
--SCN, --S(O)NHR.sub.10, --S(O).sub.2NHR.sub.10,
--NR.sub.10S(O).sub.2R.sub.10, R.sub.5, or R.sub.6, provided that
when R.sub.4 is --SO.sub.1-2R.sub.10 or --CO.sub.12R.sub.10 and
R.sub.10 is heterocycle, halogenated heterocycle or heterocycle
substituted with 1 substitutent selected from R.sub.13, a carbon in
the heterocycle is bonded to the carbon or sulfur; m is 1 or 2,
provided that when m is 2 each R.sub.4 is other than H; R.sub.5 is
a 5-membered heteroaromatic mono-cyclic moiety containing within
the ring 1-3 heteroatoms independently selected from the group
consisting of --O--, .dbd.N--, --N(R.sub.16)--, and --S--, and
having 0-1 substituent selected from R.sub.1, and further having
0-3 substituents independently selected from F, Cl, Br, or I, or
R.sub.5 is a 9-membered fused-ring moiety having a 6-membered ring
fused to a 5-membered ring and having the formula 76wherein each A
is independently CR.sub.14 or N, provided that only up to one A is
N, E.sup.1 and E.sup.2 are independently selected from CR.sub.14,
O, S, or NR.sub.16, and G is CR.sub.14, provided that R.sub.14 or
R.sub.16 can be a bond when -- forms a double bond and further
provided that only one R.sub.14 or R.sub.16 can be a bond for
bonding R.sub.5 to a moiety to which it is attached; R.sub.6 is a
6-membered heteroaromatic mono-cyclic moiety containing within the
ring 1-3 heteroatoms selected from .dbd.N-- and having 0-1
substituent selected from R.sub.9 and 0-3 substituent(s)
independently selected from F, Cl, Br, or I, or R.sub.6 is a
10-membered heteroaromatic bi-cyclic moiety containing within one
or both rings 1-3 heteroatoms selected from .dbd.N--, each
10-membered fused-ring moiety having 0-1 substituent selected from
R.sub.9, and 0-3 substituent(s) independently selected from F, Cl,
Br, or I; R.sub.7 is H, alkyl, halogenated alkyl, substituted
alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
phenyl, or phenyl having 0-4 substituents independently selected
from F, Cl, Br, I, and R.sub.9: Each R.sub.8 is independently H,
alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,
halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
halogenated heterocycloalkyl, substituted heterocycloalkyl, phenyl,
or phenyl substituted with 0-4 independently selected from F, Cl,
Br, I, or R.sub.9; R.sub.9 is alkyl, substituted alkyl, halogenated
alky, --OR.sub.11, --CN, --NO.sub.2, --NR.sub.10R.sub.10; Each
R.sub.10 is independently H, alkyl, cycloalkyl, heterocycloalkyl,
alkyl substituted with 1 substituent selected from R.sub.13,
cycloalkyl substituted with I 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, heterocycloalkyl, halogenated
alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
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, --N(R.sub.11).sub.2,
R.sub.11, --NO.sub.2, --CN(R.sub.11).sub.2, --CN,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2, or
--NR.sub.11S(O).sub.2R.sub.11; R.sub.13 is --OR.sub.11,
--SR.sub.11, --N(R.sub.11).sub.2, --C(O)R.sub.11, --SOR.sub.11,
--SO.sub.2R.sub.11, --C(O)NR.sub.11R.sub.11, --CN, --CF.sub.3,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2; Each R.sub.14 is
independently bond, H, alkyl, cycloalkyl, heterocycloalkyl,
halogenated alkyl, halogenated cycloalkyl, halogenated
heterocycloalkyl, substituted alkyl, substituted cycloalkyl,
substituted heterocycloalkyl, --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, --NR.sub.11S(O).sub.2R.sub.11, F,
Cl, Br, I, or a bond, 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,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, 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.15 is H, alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, halogenated
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated
heterocycloalkyl, or substituted heterocycloalkyl; Each R.sub.16 is
independently bond, H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, halogenated heterocycloalkyl, or substituted
heterocycloalkyl; Aryl is phenyl, substituted phenyl, naphthyl, or
substituted naphthyl; 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; 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; Alkyl is both straight- and branched-chain
moieties having from 1-6 carbon atoms; Lower alkyl is both
straight- and branched-chain moieties having from 1-4 carbon atoms;
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; Lower halogenated alkyl is an alkyl moiety having from
1-4 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; Substituted alkyl is an alkyl
moiety from 1-6 carbon atoms and having 0-3 substituents
independently selected from R.sub.5, R.sub.6, F, Cl, Br, or I 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, --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, phenyl, or phenyl having 1 substituent selected from
R.sub.9 and further having 0-3 substituents independently selected
from F, Cl, Br, or I: Lower substituted alkyl is lower alkyl having
0-3 substituents independently selected from F, Cl, Br, or I, and
further having 1 substituent selected from --OR.sub.10,
--SR.sub.10, --NR.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2, --CN, --NR.sub.10C(OR.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6, wherein each R.sub.10 is
independently H, lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl. wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF, NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11 or --NO.sub.2, and wherein each
R.sub.11 is independently H, lower alkyl, lower cycloalkyl,
heterocycloalkyl, lower halogenated alkyl, lower halogenated
cycloalkyl, or halogenated heterocycloalkyl: Alkenyl is straight-
and branched-chain moieties having from 2-6 carbon atoms and having
at least one carbon-carbon double bond: Lower alkenyl is straight-
and branched-chain moieties having from 2-4 carbon atoms and having
at least one carbon-carbon double bond: 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:
Lower halogenated alkenyl is an unsaturated alkenyl moiety having
from 2-4 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: 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 R.sub.5, R.sub.6, --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,
phenyl, or phenyl having 1 substituent selected from R.sub.9, and
further having 0-3 substituents independently selected from F, Cl,
Br, or I: Lower substituted alkenyl is lower alkenyl having 0-3
substituents independently selected from F, Cl, Br, or I, and
further having 1 substituent selected from R.sub.5, R.sub.6, --CN,
--OR.sub.10, --SR.sub.10, --N(R.sub.10), --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6, wherein each R.sub.10 is
independently H, lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl. wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11OR.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2, and wherein each
R.sub.11 is independently H, lower alkyl, lower cycloalkyl,
heterocycloalkyl, lower halogenated alkyl, lower halogenated
cycloalkyl, or halogenated heterocycloalkyl: Alkynyl is straight-
and branched-chained moieties having from 2-6 carbon atoms and
having at least one carbon-carbon triple bond: Lower alkynyl is
straight- and branched-chained moieties having from 2-6 carbon
atoms and having at least one carbon-carbon triple bond:
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: Lower halogenated alkynyl is
an unsaturated alkynyl moiety having from 3-4 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: 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 R.sub.5, R.sub.6, --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, phenyl, or phenyl having 1
substituent selected from R.sub.9, and further having 0-3
substituents independently selected from F, Cl, Br, or I: Lower
substituted alkynyl is lower alkynyl having 0-3 substituents
independently selected from F, or Cl, and further having 1
substituent selected from R.sub.5, R.sub.6, --OR.sub.10,
--SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2, --CN, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6, wherein each R.sub.10 is
independently H, lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl, wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2, and wherein each
R.sub.11 is independently H, lower alkyl, lower cycloalkyl,
heterocycloalkyl, lower halogenated alkyl, lower halogenated
cycloalkyl, or halogenated heterocycloalkyl; Cycloalkyl is a cyclic
alkyl moiety having from 3-6 carbon atoms; Halogenated cycloalkyl
is a cyclic moiety having from 3-6 carbon atoms and having 1-4
substituents independently selected from F, or Cl; 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 phenyl having 1 substituent selected from
R.sub.9, and further having 0-3 substituents independently selected
from F, Cl, Br, or I; Heterocycloalkyl is a cyclic moiety having
4-7 atoms with 1-2 atoms within the ring being --S--,
--N(R.sub.7)--, or --O--; Halogenated heterocycloalkyl is a cyclic
moiety having from 4-7 atoms with 1-2 atoms within the ring being
--S--, --N(R.sub.7)--, or --O--, and having 1-4 substituents
independently selected from F, or Cl; Substituted heterocycloalkyl
is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the
ring being --S--, --N(R.sub.7)--, or --O-- and having 0-3
substituents independently selected from --F, or --Cl, and further
having 1 substituent selected from R.sub.5, R.sub.6, --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.9 and
further having 0-3 substituents independently selected from F, Cl,
Br, or I; 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.1 where valency allows; or pharmaceutical composition,
pharmaceutically acceptable salt, racemic mixture, and pure
enantiomer thereof.
2. The method of claim 1, wherein m is 1.
3. (Cancel)
4. (Cancel)
5. The method of claim 2, wherein R.sub.2 is H, or methyl.
6. The method of claim 5, wherein W is 5-benzofuranyl,
6-benzofuranyl, 5-benzothienyl, or 6-benzothienyl, any of which is
optionally substituted with lower alkyl, lower halogenated alkyl,
lower alkynyl, halogen, cyano, aminocarbonyl, formyl, or
acetyl.
7. The method of claim 6, wherein Azabicyclo is II.
8. The method of claim 7, wherein the compound is
N-[(exo-4S)-1-azabicyclo-
[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2-
.1]hept-3-yl]-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]h-
ept-3-yl]-2-methyl-1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.-
2.1]hept-3-yl]-2-methyl-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-6-carboxam-
ide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-5-carb-
oxamide;
N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,6-dica-
rboxamide;
N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,5-di-
carboxamide;
2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofur-
an-6-carboxamide;
2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-ben-
zofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl--
1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-fo-
rmyl-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-
-3-methyl-1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept--
3-yl]-3-methyl-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]-
hept-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicycl-
o[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-6-carboxa-
mide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-5-ca-
rboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran--
6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofu-
ran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-b-
enzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethyn-
yl-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-
-prop-1-ynyl-1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]he-
pt-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;
N-[(exo-4S)-1-azabicycl-
o[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-6-carboxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-5-carboxam-
ide;
N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,6-dicarbox-
amide;
N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,5-dicarb-
oxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-6-carb-
oxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-5-carb-
oxamide;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide-
;
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-5-carboxamide;
or a pharmaceutically acceptable salt thereof.
9. The method of claim 6, wherein Azabicyclo is III and k is 1.
10. The method of claim 9, wherein the compound is
N-[(3R,5R)-1-azabicyclo-
[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1-
]oct-3-yl]-1-benzofuran-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-
-yl]-2-methyl-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oc-
t-3-yl]-2-methyl-1-benzofuran-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1-
]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2-
.1]oct-3-yl)]-2-cyano-1-benzofuran-5-carboxamide;
N-6-[(3R,5R)-1-azabicycl-
o[3.2.1]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;
N-5-[(3R,5R)-1-azabicycl-
o[3.2.1]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;
2-acetyl-N-[(3R,5R)-1-az-
abicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;
2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxami-
de;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-6-carbox-
amide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-5-car-
boxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-6--
carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-
-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benz-
ofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl--
1-benzofuran-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chlo-
ro-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-c-
hloro-1-benzofuran-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]--
3-bromo-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl-
]-3-bromo-1-benzofuran-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3--
yl]-3-ethynyl-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oc-
t-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.-
1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carb-
oxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-6-ca-
rboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-5--
carboxamide;
N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,6-di-
carboxamide;
N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,5-di-
carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-6-ca-
rboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-5-carb-
oxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-6-carboxamide;
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-5-carboxamide; or
a pharmaceutically acceptable salt thereof.
11. The method of claim 6, wherein Azabicyclo is IV and k is 1.
12. The method of claim 11, wherein the compound is
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-5-carboxamide;
N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,6-dicarboxamide;
N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,5-dicarboxamide;
2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;
2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-6-carboxami-
de;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-5-carbox-
amide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-6-carbox-
amide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-5-carbox-
amide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-5-carboxam-
ide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-5-carbox-
amide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-6-c-
arboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofura-
n-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-
-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran--
5-carboxamide;
N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,6-dic-
arboxamide;
N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,5-dicarb-
oxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-6-carboxami-
de;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-5-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-6-carboxamide;
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-5-carboxamide; or a
pharmaceutically acceptable salt thereof.
13. The method of claim 6, wherein Azabicyclo is V or VI and
R.sub.3 is H.
14. The method of claim 13, wherein the compound is
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-5-carboxamide;
N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,6-dicarboxamide;
N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,5-dicarboxamide;
2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;
2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-6-carboxamide-
;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-5-carboxamid-
e;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-5-carboxamide;
N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,6-dicarboxamide;
N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,5-dicarboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-5-carboxamide;
N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,6-dicarboxamide;
N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,5-dicarboxamide;
2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;
2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl- I
-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-5-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-6-carboxamide-
;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-5-carboxamid-
e;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-5-carboxamide;
N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,6-dicarboxamide;
N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,5-dicarboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-6-carboxamide;
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-5-carboxamide; or
pharmaceutically acceptable salt thereof.
15-22. (Delete)
23. A method for treating a disease or condition in a mammal in
need thereof, wherein the mammal would receive symptomatic relief
from the administration of an .alpha.7 nicotinic acetylcholine
receptor agonist comprising administering to the mammal a
therapeutically effective amount of a compound according to Formula
I: 77wherein Azabicyclo is 78R.sub.1 is H, alkyl, halogenated
alkyl, cycloalkyl, substituted phenyl, or substituted naphthyl;
R.sub.2 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, or aryl; W.sup.1 is O, S, or N(R.sub.15); W.sup.5 and
W.sup.6 are independently H or a bond to the carbonyl of Formula I,
provided that only one of W.sup.5 and W.sup.6 is said bond and the
other is H; Each R4 is independently H, F, Cl, Br, I, alkyl,
halogenated alkyl, substituted alkyl, alkenyl, halogenated alkenyl,
substituted alkenyl, alkynyl, halogenated alkynyl, substituted
alkynyl, cycloalkyl, halogenated cycloalkyl, substituted
cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl,
substituted heterocycloalkyl, lactam heterocylcoalkyl, phenyl,
substituted phenyl, --OR.sub.10, --SR.sub.10, --SOR.sub.10,
--SO.sub.2R.sub.10, --NR.sub.10C(O)R.sub.5, --NR.sub.10C(O)R.sub.6,
--NR.sub.10C(O)R.sub.8, --N(R.sub.10).sub.2, --NO.sub.2,
--C(O)R.sub.10, --CN, --C(O).sub.2R.sub.10, --C(O)NHR.sub.10,
--SCN, --S(O)NHR.sub.10, --S(O).sub.2NHR.sub.10,
--NR.sub.10S(O).sub.2R.s- ub.10, R.sub.5, or R.sub.6, provided that
when R4 is --SO.sub.1-2R.sub.10 or --CO.sub.1-2R.sub.10 and
R.sub.10 is heterocycle, halogenated heterocycle or heterocycle
substituted with 1 substitutent selected from R.sub.13, a carbon in
the heterocycle is bonded to the carbon or sulfur; m is 1 or 2,
provided that when m is 2 each R.sub.4 is other than H; R.sub.5 is
a 5-membered heteroaromatic mono-cyclic moiety containing within
the ring 1-3 heteroatoms independently selected from the group
consisting of --O--, .dbd.N--, --N(R.sub.16)--, and --S--, and
having 0-1 substituent selected from R.sub.9, and further having
0-3 substituents independently selected from F, Cl, Br, or I, or
R.sub.5 is a 9-membered fused-ring moiety having a 6-membered ring
fused to a 5-membered ring and having the formula 79wherein each A
is independently CR.sub.14 or N, provided that only up to one A is
N, E.sup.1 and E.sup.2 are independently selected from CR.sub.14,
O, S, or NR.sub.16, and G is CR.sub.14, provided that R.sub.14 or
R.sub.16 can be a bond when -- forms a double bond and further
provided that only one R.sub.14 or R.sub.16 can be a bond for
bonding R.sub.5 to a moiety to which it is attached; R.sub.6 is a
6-membered heteroaromatic mono-cyclic moiety containing within the
ring 1-3 heteroatoms selected from .dbd.N-- and having 0-1
substituent selected from R.sub.9 and 0-3 substituent(s)
independently selected from F, Cl, Br, or I, or R.sub.6 is a
10-membered heteroaromatic bi-cyclic moiety containing within one
or both rings 1-3 heteroatoms selected from .dbd.N--, each
10-membered fused-ring moiety having 0-1 substituent selected from
R.sub.9, and 0-3 substituent(s) independently selected from F, Cl,
Br, or I; R.sub.7 is H, alkyl, halogenated alkyl, substituted
alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
phenyl, or phenyl having 0-4 substituents independently selected
from F, Cl, Br, I, and R.sub.9; Each R.sub.8 is independently H,
alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,
halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
halogenated heterocycloalkyl, substituted heterocycloalkyl, phenyl,
or phenyl substituted with 0-4 independently selected from F, Cl,
Br, I, or R.sub.9; R.sub.9 is alkyl, substituted alkyl, halogenated
alky, --OR.sub.11, --CN, -NO.sub.2, --NR.sub.10R.sub.10; 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 I 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, heterocycloalkyl, halogenated
alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
R.sub.12, --OR.sub.11, --SR.sub.11, alkyl, cycloalkyl,
heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,
halogenated heterocycloalkyl, substituted alkyl, substituted
cycloalkyl, substituted heterocycloalkyl, --N(R.sub.11).sub.2,
--C(O)R.sub.11, --NO.sub.2, --C(O)N(R.sub.11).sub.2, --CN,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2, or
--NR.sub.11S(O).sub.2R.sub.11, R.sub.13 is --OR.sub.11,
--SR.sub.11, --N(R.sub.11).sub.2, --C(O)R.sub.11, --SOR.sub.11,
--SO.sub.2R.sub.11, --C(O)NR.sub.11R.sub.11, --CN, --CF.sub.3,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2; Each R.sub.14 is
independently bond, H, alkyl, cycloalkyl, heterocycloalkyl,
halogenated alkyl, halogenated cycloalkyl, halogenated
heterocycloalkyl, substituted alkyl, substituted cycloalkyl,
substituted heterocycloalkyl, --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, --NR.sub.11S(O).sub.2R.sub.11F, Cl,
Br, I, or a bond, 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,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, 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.15 is H, alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, halogenated
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated
heterocycloalkyl, or substituted heterocycloalkyl; Each R.sub.16 is
independently bond, H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, halogenated heterocycloalkyl, or substituted
heterocycloalkyl; Aryl is phenyl, substituted phenyl, naphthyl, or
substituted naphthyl; 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; 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; Alkyl is both straight- and branched-chain
moieties having from 1-6 carbon atoms; Lower alkyl is both
straight- and branched-chain moieties having from 1-4 carbon atoms;
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; Lower halogenated alkyl is an alkyl moiety having from
1-4 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; Substituted alkyl is an alkyl
moiety from 1-6 carbon atoms and having 0-3 substituents
independently selected from R.sub.5, R.sub.6, F, Cl, Br, or I 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- , --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, phenyl, or phenyl having 1 substituent selected from
R.sub.9 and further having 0-3 substituents independently selected
from F, Cl, Br, or I; Lower substituted alkyl is lower alkyl having
0-3 substituents independently selected from F, Cl, Br, or I, and
further having 1 substituent selected from --OR.sub.10,
--SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2- , --CN, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6, wherein each R.sub.10 is
independently H, lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl, wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2, and wherein each
R.sub.11 is independently H, lower alkyl, lower cycloalkyl,
heterocycloalkyl, lower halogenated alkyl, lower halogenated
cycloalkyl, or halogenated heterocycloalkyl; Alkenyl is straight-
and branched-chain moieties having from 2-6 carbon atoms and having
at least one carbon-carbon double bond; Lower alkenyl is straight-
and branched-chain moieties having from 2-4 carbon atoms and having
at least one carbon-carbon double bond; 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;
Lower halogenated alkenyl is an unsaturated alkenyl moiety having
from 2-4 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; 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 R.sub.5, R.sub.6, --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,
phenyl, or phenyl having 1 substituent selected from R.sub.9, and
further having 0-3 substituents independently selected from F, Cl,
Br, or I; Lower substituted alkenyl is lower alkenyl having 0-3
substituents independently selected from F, Cl, Br, or I, and
further having 1 substituent selected from R.sub.5, R.sub.6, --CN,
--OR.sub.10, --SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2- , --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6, wherein each R.sub.10 is
independently H, lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl, wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11or --NO.sub.2, and wherein each
R.sub.11 is independently H, lower alkyl, lower cycloalkyl,
heterocycloalkyl, lower halogenated alkyl, lower halogenated
cycloalkyl, or halogenated heterocycloalkyl; Alkynyl is straight-
and branched-chained moieties having from 2-6 carbon atoms and
having at least one carbon-carbon triple bond; Lower alkynyl is
straight- and branched-chained moieties having from 2-6 carbon
atoms and having at least one carbon-carbon triple bond;
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; Lower halogenated alkynyl is
an unsaturated alkynyl moiety having from 3-4 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; 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 R.sub.5, R.sub.6, --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, phenyl, or phenyl having 1
substituent selected from R.sub.9, and further having 0-3
substituents independently selected from F, Cl, Br, or I; Lower
substituted alkynyl is lower alkynyl having 0-3 substituents
independently selected from F, or Cl, and further having 1
substituent selected from R.sub.5, R.sub.6, --OR.sub.10,
--SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2, --CN, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6, wherein each R.sub.10 is
independently H, lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl, wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2, and wherein each
R.sub.11 is independently H, lower alkyl, lower cycloalkyl,
heterocycloalkyl, lower halogenated alkyl, lower halogenated
cycloalkyl, or halogenated heterocycloalkyl; Cycloalkyl is a cyclic
alkyl moiety having from 3-6 carbon atoms: Halogenated cycloalkyl
is a cyclic moiety having from 3-6 carbon atoms and having 1-4
substituents independently selected from F, or Cl; 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 phenyl having 1 substituent selected from
R.sub.9, and further having 0-3 substituents independently selected
from F, Cl, Br, or I; Heterocycloalkyl is a cyclic moiety having
4-7 atoms with 1-2 atoms within the ring being --S--,
--N(R.sub.7)--, or --O--; Halogenated heterocycloalkyl is a cyclic
moiety having from 4-7 atoms with 1-2 atoms within the ring being
--S--, --N(R.sub.7)--, or --O--, and having 1-4 substituents
independently selected from F, or Cl; Substituted heterocycloalkyl
is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the
ring being --S--, --N(R.sub.7)--, or --O-- and having 0-3
substituents independently selected from --F, or --Cl, and further
having 1 substituent selected from R.sub.5, R.sub.6, --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.9 and
further having 0-3 substituents independently selected from F, Cl,
Br, or I; 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.9 where valency allows: or pharmaceutical composition,
pharmaceutically acceptable salt, racemic mixture, or pure
enantiomer thereof.
24. The method of claim 23, wherein R.sub.1 is H, lower alkyl, or
cycloalkyl.
25. (Delete)
26. The method of claim 24, wherein R.sub.2 is H, or methyl.
27. The method of claim 26, wherein m is 1 and W is 5-benzofuranyl,
6-benzofuranyl, 5-benzothienyl, or 6-benzothienyl, any of which is
optionally substituted with lower alkyl, lower halogenated alkyl,
lower alkynyl, halogen, cyano, aminocarbonyl, formyl, or
acetyl.
28. (Delete)
29. The method of claim 27, wherein the compound is
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-5-carboxamide;
N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;
N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;
2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;
2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxami-
de;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-carbox-
amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carbox-
amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-5-carbox-
amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxam-
ide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-6-carboxa-
mide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carbox-
amide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-c-
arboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofura-
n-5-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-
-6-carboxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran--
5-carboxamide;
N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,6-dic-
arboxamide;
N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarb-
oxamide;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxami-
de;
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide;
or a pharmaceutically acceptable salt thereof.
30. The method of claim 27, wherein the compound is
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxami-
de;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carbox-
amide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofu-
ran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-meth-
yl-1-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct--
3-yl]-2-cyano-1-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-(1-azabicycl-
o[2.2.2]oct-3-yl)]-2-cyano-1-benzofuran-5-carboxamide;
N-6-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicar-
boxamide;
N-5-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran--
2,5-dicarboxamide;
2-acetyl-N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-y-
l]-1-benzofuran-6-carboxamide;
2-acetyl-N-[(2S,3R)-2-methyl-1-azabicyclo[2-
.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicycl-
o[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-5--
carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-b-
enzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]--
3-methyl-1-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.-
2]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-
-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro--
1-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-y-
l]-3-chloro-1-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2-
.2.2]oct-3-yl]-3-bromo-1-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-a-
zabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-6-
-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-
-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl-
]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyc-
lo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-6-c-
arboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-ben-
zofuran-5-carboxamide;
N-6-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]--
1-benzofuran-3,6-dicarboxamide;
N-5-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]o-
ct-3-yl]-1-benzofuran-3,5-dicarboxamide;
N-[(2S,3R)-2-methyl-1-azabicyclo[-
2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide;
N-[(2S,3R)-2-methyl-1-azab-
icyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide; or
pharmaceutically acceptable salt thereof.
31-44. (Delete)
45. The method of claim 1, wherein the disease or condition is
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, amyotrophic lateral sclerosis, borderline
personality disorder, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, tardive dyskinesia, Pick's disease,
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,
age-related macular degeneration, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
46. The method of claim 1, wherein the disease or condition is
attention deficit disorder, or attention deficit hyperactivity
disorder.
47. The method of claim 1, wherein the disease or condition is
depression, general anxiety disorder, or post traumatic stress
disorder.
48. The method of claim 1, wherein the disease or condition is
cognitive and attention deficit symptoms of Alzheimer's,
neurodegeneration associated with diseases such as Alzheimer's
disease, pre-senile dementia, or senile dementia.
49. The method of claim 1, wherein the disease or condition is
schizophrenia or psychosis.
50. The method of claim 8, wherein the disease or condition is
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, or symptoms associated with pain.
51. The method of claim 10, wherein the disease or condition is
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, or symptoms associated with pain.
52. The method of claim 12, wherein the disease or condition is
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, or symptoms associated with pain.
53. The method of claim 23, wherein the disease or condition is
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, amyotrophic lateral sclerosis, borderline
personality disorder, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, tardive dyskinesia, Pick's disease,
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,
age-related macular degeneration, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
54. The method of claim 23, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, depression, general anxiety disorder, post traumatic
stress disorder, cognitive and attention deficit symptoms of
Alzheimer's, neurodegeneration associated with diseases such as
Alzheimer's disease, pre-senile dementia, senile dementia,
schizophrenia, psychosis, or symptoms associated with pain.
55. The method of claim 23, wherein the disease or condition is
attention deficit disorder, or attention deficit hyperactivity
disorder.
56. The method of claim 23, wherein the disease or condition is
depression, general anxiety disorder, or post traumatic stress
disorder.
57. The method of claim 23, wherein the disease or condition is
cognitive and attention deficit symptoms of Alzheimer's,
neurodegeneration associated with diseases such as Alzheimer's
disease, pre-senile dementia, or senile dementia.
58. The method of claim 23, wherein the disease or condition is
schizophrenia or psychosis.
59. The method of claim 29, wherein the disease or condition is
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, or symptoms associated with pain.
60. The method of claim 29, wherein the disease or condition is
attention deficit disorder, attention deficit hyperactivity
disorder, depression, general anxiety disorder, post traumatic
stress disorder, cognitive and attention deficit symptoms of
Alzheimer's, neurodegeneration associated with diseases such as
Alzheimer's disease, pre-senile dementia, senile dementia,
schizophrenia, psychosis, or symptoms associated with pain.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Serial No. 60/357926 filed on 19 February 2002, under
35 USC 1 19(e)(i), which is 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.
[0003] The invention also concerns the synthesis of and isolation
of intermediates and final compounds. Specifically, the present
invention concerns the selective synthesis of
(3R,5R)-1-azabicyclo[3.2.1]octan-3-am- ine or salts thereof.
BACKGROUND OF THE INVENTION
[0004] 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.
[0005] 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, J. Neurochem., 1997, 68(5):2140-51). 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.
[0006] 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.
[0007] U.S. Pat. No. 5,977,144 discloses compositions for
benzylidene- and cinnamylidene-anabaseines and methods for using
these compositions for treating conditions associated with defects
or malfunctioning of nicotinic subtypes brain receptors. These
compositions target the .alpha.7 receptor subtype with little or no
activation of the .alpha.4.beta.2 or other receptor subtypes.
[0008] U.S. Pat. No. 5,599,937 discloses heteroaromatic
quinuclidines used for treating diseases related to muscarinic
receptor function.
[0009] U.S. Pat. No. 5,561,149 discloses the use of a mono or
bicyclic carbocyclic, or heterocyclic carboxylic acid, ester or
amide or an imidazolyl carbazol in the manufacture of a medicament
suitable for the treatment of stress-related psychiatric disorders,
for increasing vigilance, for the treatment of rhinitis or
serotonin-induced disorders and/or coadministration with another
active agent to increase the bioavailability thereof, or for nasal
administration.
[0010] U.S. Pat. No. 5,543,426 discloses the use of certain
3,7-disubstituted indole compounds for treating depression or
cognitive disorders.
[0011] U.S. Pat. No. 5,434,161 discloses imidazopyridines as
serotonergic 5-HT.sub.3 antagonists.
[0012] U.S. Pat. No. 5,362,740 discloses dihydrobenzofuran
carboxamides useful in treating CNS disorders, but motility
disorders, and/or emisis and/or pain in mammals, and/or
migraine.
[0013] U.S. Pat. No. 5,352,685 discloses thieno[3,2-b]pyridine
derivatives effective for the prevention and therapeutical
treatment of the symptoms caused by gastric hypanakinesis, such as
heartburn, abdominal distension feeling, anorexia, unpleasant
feeling on upper abdomen, abdominalgia, nausea, vomiting, etc.
caused by the underlying diseases such as acute and chronic
gastritis, stomach and duodenum ulcer, gastroneurosis,
gastroptosis, etc.
[0014] U.S. Pat. No. 5,342,845 discloses indole derivatives and
drugs. The compound of the invention is disclosed as being
effective as a gastrointestinal motor activity regulator,
antimigraine, antipsychotic or antianxiety drug and for dementia or
orthostatic hypotension.
[0015] U.S. Pat. No. 5,322,951 discloses certain
1-(2,3-dihydro-indole)car- bonyl intermediates useful for preparing
1-(2,3-dihydro)-1-carboxamide final products that possess 5-HT
M-receptor antagonist activity.
[0016] U.S. Pat. No. 5,272,154 discloses 3,7 substituted indole and
indazole compounds and pharmaceutical compositions containing them
and are disclosed as being useful for the treatment of psychiatric
disorders.
[0017] U.S. Pat. No. 5,217,975 discloses azabicyclic compounds for
treating dementia.
[0018] U.S. Pat. No. 5,114,947 discloses a method for alleviating
anxiety using benzobicyclic carboxamides.
[0019] U.S. Pat. No. 5,039,680 discloses 5-HT.sub.3 antagonists in
preventing or reducing dependency on dependency-inducing
agents.
[0020] U.S. Pat. No. 5,001,133 discloses substituted benzoic acid
heterocyclic amides and esters as being serotonin M
antagonists.
[0021] U.S. Pat. No. 4,985,437 discloses the use of certain
compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at
5-HT.sub.3 receptors for the treatment of cognitive disorders such
as attentional and memory deficits and dementia states.
[0022] U.S. Pat. No. 4,983,600 discloses heterocyclic compounds
useful as 5-HT.sub.3 antagonists.
[0023] U.S. Pat. No. 4,973,594 discloses the use of compounds which
act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT.sub.3
receptors for the treatment of depression.
[0024] U.S. Pat. No. 4,937,247 discloses 1-acyl indazoles that are
disclosed as having 5-HT.sub.3 antagonist activity.
[0025] U.S. Pat. No. 4,935,511 discloses benzoxazine and
benzoxazepin carboxamide 5-HT.sub.3 antagonists properties
including CNS, anti-emetic and gastric prokinetic activity and
which are void of any significant D.sub.2 receptor binding
affinity.
[0026] U.S. Pat. No. 4,921,982 discloses
5-halo-2,3-dihydro-2,2-dimethylbe- nzofuran-7-carboxylic acids
which are useful as intermediates for 5-HT.sub.3 antagonists.
[0027] U.S. Pat. No. 4,920,219 discloses substituted saturated and
unsaturated indole quinoline and benzazepine carboxamides and their
valuable use as 5-HT.sub.3 antagonists having CNS and gastric
prokinetic activity void of any significant D.sub.2 receptor
binding properties.
[0028] U.S. Pat. No. 4,920,127 discloses substituted indoles and
their use as 5-HT.sub.3 receptor antagonists.
[0029] U.S. Pat. No. 4,910,193 discloses treatment of
gastrointestinal disorders.
[0030] U.S. Pat. No. 4,888,353 discloses carboxamides useful as
antiemetic or antipsychotic agents.
[0031] U.S. Pat. No. 4,882,327 discloses certain heterocyclic
N-substituted carboxamides having 5-HT.sub.3 receptor antagonist
activity.
[0032] U.S. Pat. No. 4,845,092 discloses a method of treatment of
visceral pain in mammals, including humans.
[0033] U.S. Pat. No. 4,835,162 discloses agonists and antagonists
to nicotine as smoking deterrents.
[0034] U.S. Pat. No. 4,822,795 discloses pharmaceutically useful
esters and amides.
[0035] U.S. Pat. No. 4,803,199 discloses pharmaceutically useful
heterocyclic acid esters and amides or alkylene bridged peperidines
as serotonin M antagonists.
[0036] U.S. Pat. No. 4,798,829 discloses 1-azabicyclo[3.2.2]nonane
derivatives having gastric motility enhancing activity and/or
anti-emetic activity and/or 5-HT receptor antagonist activity.
[0037] U.S. Pat. No. 4,797,406 discloses amides and esters
containing bridged piperidines and use as serotonin M
antagonists.
[0038] U.S. Pat. No. 4,721,720 discloses a method of treating
emesis, anxiety and/or irritable bowl syndrome.
[0039] U.S. Pat. No. 4,612,319 discloses bridged
quinolizinidinylamides, compositions containing them and methods
for their use.
[0040] U.S. Pat. No. 4,605,652 discloses a method of enhancing
memory or correcting memory deficiency with arylamido (and
arylthioamido)-azabicycl- oalkanes, and the pharmaceutically
acceptable acid addition salts, hydrates and alcoholates
thereof.
[0041] WO 01/76576 A2 discloses a pharmaceutical composition for
treatment of acute, chronic pain and/or neuropathic pain and
migraines.
[0042] WO 01/60821 A1 discloses novel biarylcarboxamides and their
use in therapy, especially in the treatement of prophylaxis of
psychotic and intellectual impairment conditions.
[0043] WO 01/36417 A1 discloses novel N-azabicyclo-amide
derivatives and use in therapy, especially in the treatment of
prophylaxis of psychotic disorders and intellectual impairment
disorders.
[0044] 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.
[0045] WO 99/20633 discloses benzoazine derivatives having an
antagonist activity for 5-HT.sub.3/5-HT.sub.4 receptors.
[0046] WO 97/35860 discloses novel benzimidazol derivatives having
an affinity for the serotoninergic 5-HT.sub.3/5-HT.sub.4
receptors.
[0047] WO 96/33186 discloses substituted dihydrobenzofuran
derivatives as 5-HT.sub.4 agonists.
[0048] WO 95/27490 discloses serotonin antagonists (5-HT.sub.3) for
treating fibromyalgia.
[0049] WO 95/04742 discloses tropyl 7-azaindol-3-ylcarboxyamides as
antitussive agents.
[0050] WO 92/10494 discloses novel compounds that are 5-HT.sub.3
receptor antagonists.
[0051] WO 91/17161 discloses isoquinoline amides and esters as
5-HT.sub.3 receptor antagonists.
[0052] WO 91/09593 discloses 5-HT.sub.3 antagonists for treatment
of nausea, bradycardia or hypotension associated myocardial
instability.
[0053] WO 90/14347 A as abstracted in chemical abstract
1991:143,158 discloses N-quinuclidinyl-indolecarboxamide
derivatives as being antiemetics.
[0054] EP 512 350 A2 discloses 3-(indolyl-2-carboxamido)
quinuclidines useful for treating diseases characterized by an
excess or enhanced sensitivity to serotonin, e.g., psychosis,
nausea, vomiting, dementia or other cognitive diseases, migraine,
diabetes. The compound may be used to control anxiety, aggression,
depression, and pain. The compounds are disclosed as serotonin
5-HT.sub.3 antagonists.
[0055] EP 496 064 A1 discloses a process for the preparation of
substituted benzofuran derivatives. The compounds are disclosed as
being useful 5-HT.sub.3 receptor antagonists.
[0056] EP 483 836 A1 discloses pyrazolo[1,5-a]pyridine-3-carboxylic
acid derivatives, their preparation process, and serotonin receptor
antagonists containing them as active ingredients.
[0057] DE 3810552 A1 discloses esters and amides of indolyl-,
benzo[b]thiophenyl-, benzo[b]furancarboxylic acids or 4-amino-2
methoxy-benzoic acids with N-heterocyclic or N-heterobicyclic
alcohols or amines. The compounds disclosed have activity against
pain especially migraine, as an anti-arrhythmic for
gastrointestinal disturbances, stomach disturbances, gastritis
ulcer, gall bladder, spastic colon, Crohn's disease, ulcerative
colitis, carcinoid syndrome, diarrhea of various types. The
compounds are also disclosed as speeding stomach emptying,
controlling gastro duodenal and gastro esophageal reflux,
disturbances of esophageal motility, hiatal hernia, cardiac
insufficiency, hypotonic stomach, paralytic ileus, manic depressive
psychosis and other psychoses. The compounds are also disclosed as
useful for stress related diseases, senility, and enhancement of
nasal absorption of other agents, e.g., in the treatment of
emesis.
[0058] In Bioorg. & Med.Chem. Lett. 11 (2001) 319-321, the
5-HT.sub.3 antagonist tropisetron (ICS 205-930) is discussed as a
potent and selective x7 nicotinic receptor partial agonist.
[0059] In Behavioral Brain Res., 113 (2000) 169-181, it is
discussed that the brain .alpha.7 nicotinic receptor may be an
important therapeutic target for the treatment of Alzheimer's
disease using DMXBA which is known as GTS-21.
[0060] In Bioorg. & Med. Chem. Lett. 9 (1999) 1895-1900, it is
discussed the discovery of a highly potent, functionally-selective
muscarinic M.sub.1 agonist.
[0061] In Bioorg. & Med. Chem. Lett. 4 (1994) 695-698, it is
discussed pyrazolo[1,5-a]pyridines and pyrazolo[1,5-b]pyridazines
as 5-HT.sub.3 antagonists.
[0062] In Eur. J.Med. Chem., 34 (1999) 415-422,
benzimidazole-2-carboxylic acid amides and esters are discussed as
a new structural class of 5-HT.sub.3 ligands.
SUMMARY OF THE INVENTION
[0063] The present invention discloses compounds of the Formula I:
3
[0064] wherein Azabicyclo is 4
[0065] R.sub.1 is H, alkyl, halogenated alkyl, cycloalkyl,
substituted phenyl, or substituted naphthyl;
[0066] R.sub.2 is H, F, Cl, Br, I, alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl;
[0067] k is 1 or 2, provided that when k is 2, each R.sub.2 is
other than H;
[0068] R.sub.3 is H, lower alkyl, lower substituted alkyl, or lower
halogenated alkyl;
[0069] W.sub.1 is O, S, or N(R.sub.15);
[0070] W.sup.5 and W.sup.6 are independently H or a bond to the
carbonyl of Formula I, provided that only one of W.sup.5 and
W.sup.6 is said bond and the other is H;
[0071] Each R.sub.4 is independently H, F, Cl, Br, I, alkyl,
halogenated alkyl, substituted alkyl, alkenyl, halogenated alkenyl,
substituted alkenyl, alkynyl, halogenated alkynyl, substituted
alkynyl, cycloalkyl, halogenated cycloalkyl, substituted
cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl,
substituted heterocycloalkyl, lactam heterocylcoalkyl, phenyl,
substituted phenyl, --OR.sub.10, --SR.sub.10, --SOR.sub.10,
--SO.sub.2R.sub.10, --NR.sub.10C(O)R.sub.5, --NR.sub.10C(O)R.sub.6,
--NR.sub.10C(O)R.sub.8, --NR.sub.10C(O)R.sub.10,
--N(R.sub.10).sub.2, --NO.sub.2, --C(O)R.sub.10, --CN,
--C(O).sub.2R.sub.10, --C(O)NHR.sub.10, --SCN, --S(O)NHR.sub.10,
--S(O).sub.2NHR.sub.10, --NR.sub.10S(O).sub.2R.sub.10, R.sub.5, or
R.sub.6, provided that when R.sub.4 is --SO.sub.1-2R.sub.10 or
--CO.sub.1-2R.sub.10 and R.sub.10 is heterocycle, halogenated
heterocycle or heterocycle substituted with 1 substitutent selected
from R.sub.13, a carbon in the heterocycle is bonded to the carbon
or sulfur;
[0072] m is 1 or 2, provided that when m is 2 each R.sub.4 is other
than H;
[0073] R.sub.5 is a 5-membered heteroaromatic mono-cyclic moiety
containing within the ring 1-3 heteroatoms independently selected
from the group consisting of --O--, .dbd.N--, --N(R.sub.16)--, and
--S--, and having 0-1 substituent selected from R.sub.9, and
further having 0-3 substituents independently selected from F, Cl,
Br, or I,
[0074] or R.sub.5 is a 9-membered fused-ring moiety having a
6-membered ring fused to a 5-membered ring and having the formula
5
[0075] wherein each A is independently CR.sub.14 or N, provided
that only up to one A is N, E.sup.1 and E.sup.2 are independently
selected from CR.sub.14, O, S, or NR.sub.16, and G is CR.sub.14,
provided that R.sub.14 or R.sub.16 can be a bond when--forms a
double bond and further provided that only one R.sub.14 or R.sub.16
can be a bond for bonding R.sub.5 to a moiety to which it is
attached;
[0076] R.sub.6 is a 6-membered heteroaromatic mono-cyclic moiety
containing within the ring 1-3 heteroatoms selected from .dbd.N--
and having 0-1 substituent selected from R.sub.9 and 0-3
substituent(s) independently selected from F, Cl, Br, or I,
[0077] or R.sub.6 is a 10-membered heteroaromatic bi-cyclic moiety
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.9, and 0-3 substituent(s)
independently selected from F, Cl, Br, or I;
[0078] R.sub.7 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl,
or phenyl having 0-4 substituents independently selected from F,
Cl, Br, I, and R.sub.9;
[0079] Each R.sub.8 is independently H, alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted
cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,
substituted heterocycloalkyl, phenyl, or phenyl substituted with
0-4 independently selected from F, Cl, Br, I, or R.sub.9;
[0080] R.sub.9 is alkyl, substituted alkyl, halogenated alky,
--OR.sub.11, --CN, --NO.sub.2, --NR.sub.10R.sub.10;
[0081] 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;
[0082] Each R.sub.11 is independently H, alkyl, cycloalkyl,
heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or
halogenated heterocycloalkyl;
[0083] 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, --N(R.sub.11).sub.2,
--C(O)R.sub.11, --NO.sub.2, --C(O)N(R.sub.11).sub.2, --CN,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2, or
--NR.sub.11S(O).sub.2R.sub.11;
[0084] R.sub.13 is --OR.sub.11, --SR.sub.11, --N(R.sub.11).sub.2,
--C(O)R.sub.11, --SOR.sub.11, --SO.sub.2R.sub.11,
--C(O)NR.sub.11R.sub.11- , --CN, --CF.sub.3,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2- ,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2;
[0085] Each R.sub.14 is independently bond, H, alkyl, cycloalkyl,
heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,
halogenated heterocycloalkyl, substituted alkyl, substituted
cycloalkyl, substituted heterocycloalkyl, --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, --NR.sub.11S(O).sub.2R.sub.11, F,
Cl, Br, I, or a bond, 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,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, 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;
[0086] R.sub.15 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, halogenated heterocycloalkyl, or substituted
heterocycloalkyl;
[0087] Each R.sub.16 is independently bond, H, alkyl, halogenated
alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl,
substituted cycloalkyl, heterocycloalkyl, halogenated
heterocycloalkyl, or substituted heterocycloalkyl;
[0088] or pharmaceutical composition, pharmaceutically acceptable
salt, racemic mixture, or pure enantiomer thereof.
[0089] Embodiments of the invention may include one or more or
combination of the following.
[0090] The present invention also includes a method to treat using
a compound according to Formula I or pharmaceutically acceptable
salt thereof, or use of a compound according to Formula I or
pharmaceutically acceptable salt thereof to prepare a medicament
for treating, a disease or condition, wherein the mammal would
receive symptomatic relief from the administration of a
therapeutically effective amount of .alpha.7 nicotinic
acetylcholine receptor agonist.
[0091] The compounds of Formula I are used to treat, or make a
medicament to treat, a disease or condition, wherein the disease or
condition is any one or more or combination of the following:
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, depression, anxiety,
general anxiety disorder, post traumatic stress disorder, mood and
affective disorders, amyotrophic lateral sclerosis, borderline
personality disorder, traumatic brain injury, behavioral and
cognitive problems in general and associated with brain tumors,
AIDS dementia complex, dementia associated with Down's syndrome,
dementia associated with Lewy Bodies, Huntington's disease,
Parkinson's disease, tardive dyskinesia, Pick's disease,
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,
age-related macular degeneration, glaucoma, neurodegeneration
associated with glaucoma, or symptoms associated with pain.
[0092] The compounds of Formula I are used to make pharmaceutical
composition(s) comprising a compound of Formula I, a
pharmaceutically acceptable excipient, and optionally
anti-psychotic agent(s), e.g., at least one anti-psychotic agent.
The pharmaceutical composition(s) is administered so the compound
of Forumla I and the agent if it is present are to be independently
administered rectally, topically, orally, sublingually, or
parenterally for a therapeutically effective interval. The compound
of Formula I is administered in an amount of from about 0.001 to
about 100 mg/kg of body weight of said mammal per day, including
from about 0.1 to about 50 mg/kg of body weight of said mammal per
day. One of ordinary skill in the art will know how to administer
the anti-psychotic agent(s).
[0093] 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 drug(s), e.g., at least one anti-psychotic agent. 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.
[0094] The compounds of Formula I (Azabicyclo is I) have asymmetric
center(s) on the quinuclidine ring. The compounds of the present
invention include quinuclidines with the 3R configuration, 3R,2S
configuration, 3S configuration, or 3S configuration without a
specific configuration at C-2, and also includes racemic mixtures,
the separate stereoisomers, and compositions of varying degrees of
stereochemical purity. For example, and not by limitation,
compounds of Formula I include compounds with stereospecificity
including: 6
[0095] The compounds of Formula I (Azabicyclo is II) have
asymmetric center(s) on the [2.2.1] azabicyclic ring at C3 and C4.
The scope of this invention includes racemic mixtures of varying
degrees of stereochemical purities, the separate stereoisomers, and
compositions of varying degrees of stereochemical purities of
Formula I being endo-4S, endo-4R, exo-4S, exo-4R: 7
[0096] The endo isomer is the isomer where the non-hydrogen
substituent at C3 of the [2.2.1] azabicyclic compound is projected
toward the larger of the two remaining bridges. The exo isomer is
the isomer where the non-hydrogen substituent at C3 of the [2.2.1]
azabicyclic compound is projected toward the smaller of the two
remaining bridges. Thus, there can be four separate isomers:
exo-4(R), exo-4(S), endo-4(R), and endo-4(S).
[0097] The compounds of Formula I (Azabicyclo is III) have
asymmetric center(s) on the [3.2.1] azabicyclic ring at C3 and C5.
The scope of this invention includes racemic mixtures of varying
degrees of stereochemical purities, the separate stereoisomers, and
compositions of varying degrees of stereochemical purities of
Formula I being endo-3S, 5R, endo-3R, 5S, exo-3R, 5R, exo-3S, 5S:
8
[0098] The compounds of Formula I (Azabicyclo is IV) have
asymmetric centers on the [3.2.2] azabicyclic ring with one center
being at C3 when R.sub.2 is absent. The scope of this invention
includes racemic mixtures of varying degrees of stereochemical
purities, the separate stereoisomers, and compositions of varying
degrees of stereochemical purities of Formula I being 3(S) and
3(R): 9
[0099] The compounds of Formula I (Azabicyclo V) have asymmetric
center(s) on the [2.2.1] azabicyclic ring at C1, C4 and C5. The
scope of this invention includes racemic mixtures of varying
degrees of stereochemical purities, the separate stereoisomers, and
compositions of varying degrees of stereochemical purities of
Formula I being (1R,4R,5S), (1R,4R,5R), (1S,4S,5R), (1S,4S,5S):
10
[0100] The endo isomer is the isomer where the non-hydrogen
substituent at C5 of the [2.2.1] azabicyclic compound is projected
toward the larger of the two remaining bridges. The exo isomer is
the isomer where the non-hydrogen substituent at C5 of the [2.2.1]
azabicyclic compound is projected toward the smaller of the two
remaining bridges. Thus, there can be four separate isomers:
exo-(1R,4R,5S), exo-(1S,4S,5R), endo-(1S,4S,5S),
endo-(1R,4R,5R).
[0101] The compounds of Formula I (Azabicyclo VI) have asymmetric
center(s) on the [2.2.1] azabicyclic ring at C1, C4 and C6. The
scope of this invention includes racemic mixtures of varying
degrees of stereochemical purities, the separate stereoisomers, and
compositions of varying degrees of stereochemical purities of
Formula I being exo-(1S,4R,6S), exo-(1R,4S,6R), endo-(1S,4R,6R),
and endo-(1R,4S,6S): 11
[0102] The endo isomer is the isomer where the non-hydrogen
substituent at C6 of the [2.2.1] azabicyclic compound is projected
toward the larger of the two remaining bridges. The exo isomer is
the isomer where the non-hydrogen substituent at C6 of the [2.2.1]
azabicyclic compound is projected toward the smaller of the two
remaining bridges. Thus, there can be four separate isomers:
exo-(1S,4R,6S), exo-(1R,4S,6R), endo-(1S,4R,6R), and
endo-(1R,4S,6S).
[0103] The compounds of the present invention having the specified
stereochemistry have different levels of activity and that for a
given set of values for the variable substitutuents one isomer may
be preferred over the other isomers. 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 when the
Azabicyclo is substituted with only the amide or is substituted
with substituents in addition to the amide, e.g., R.sub.2 is alkyl.
When racemic mixtures and compositions are referenced, it is meant
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
enantiomerically pure materials. Suitable stereoselective synthetic
procedures for producing enantiomerically pure materials are well
known in the art, as are procedures for purifying racemic mixtures
into enantiomerically pure fractions.
[0104] Stereoselective syntheses and/or subjecting the reaction
product to appropriate purification steps produces substantially
enantiomerically pure materials. Suitable stereoselective synthetic
procedures for producing enantiomerically pure materials are well
known in the art, as are procedures for purifying racemic mixtures
into enantiomerically pure fractions.
[0105] The compound of Formula I, where Azabicyclo is any one or
more of the following: I, II, III, IV, V, or VI.
[0106] Another embodiment of the compounds of Formula I includes
any one or more or combination of the following configurations for
Azabicyclo: 12
[0107] where (i) the compound is a mixture of diastereomers,
[0108] (ii) the compound has the R absolute stereochemistry at
C-3,
[0109] (iii) the compound has the R absolute stereochemistry at C-3
and the S absolute stereochemistry at C-2 as discussed herein and
R.sub.2 is other than H,
[0110] (iv) the compound has the S absolute stereochemistry at C-3,
or
[0111] (v) the compound has the S absolute stereochemistry at C-3
and is a mixture of diastereomers at C-2 as discussed herein and
R.sub.2 is other than H.
[0112] Another embodiment of compounds of Formula I includes any
one or more or combination of the following configurations for
Azabicyclo: 13
[0113] where (i) R.sub.2 is H;
[0114] (ii) R.sub.2 is alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, or aryl;
[0115] (iii) R.sub.2 is alkyl, halogenated alkyl, substituted
alkyl, cycloalkyl, or aryl; or
[0116] (iv) the 2.2.1 moiety has the exo-4(S) absolute
stereochemistry as discussed herein and R.sub.2 can have any
definition discussed herein.
[0117] Another embodiment of compounds of Formula I includes any
one or more or combination of the following configurations for
Azabicyclo: 14
[0118] where (i) R.sub.2 is H;
[0119] (ii) R.sub.2 is F, Cl, Br, I, alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl; or
[0120] (iii) R.sub.2 is alkyl, halogenated alkyl, substituted
alkyl, cycloalkyl, or aryl.
[0121] Another embodiment of compounds of Formula I includes any
one or more or combination of the following configurations for
Azabicyclo: 15
[0122] where (i) R.sub.2 is H;
[0123] (ii) R.sub.2 is F, Cl, Br, I, alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl; or
[0124] (iii) R.sub.2 is alkyl, halogenated alkyl, substituted
alkyl, cycloalkyl, or aryl.
[0125] Another embodiment of compounds of Formula I includes any
one or more or combination of the following configurations for
Azabicyclo: 16
[0126] where (i) R.sub.2 is H and k is 1;
[0127] (ii) R.sub.2 is H and where the Azabicyclo has the absolute
stereochemistry of 3R, 5R;
[0128] (iii) k is 2, where R.sub.2-a is alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl, and where R.sub.2-b is F,
Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,
or aryl;
[0129] (iv) k is 1, where R.sub.2 is alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl; or
[0130] (v) k is 1, where R.sub.2 is F, Cl, Br, I, alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, or aryl.
[0131] Another embodiment of compounds of Formula I includes any
one or more or combination of the following configurations for
Azabicyclo: 17
[0132] where (i) R.sub.2 is H and k is 1;
[0133] (ii) k is 2, where each R.sub.2-a is alkyl, halogenated
alkyl, substituted alkyl, cycloalkyl, or aryl and where each
R.sub.2-b is F, Cl, Br, I, alkyl, halogenated alkyl, substituted
alkyl, cycloalkyl, or aryl;
[0134] (iii) k is 1, where R.sub.2 is alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl; or
[0135] (iv) k is 1, where R.sub.2 is F, Cl, Br, I, alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, or aryl.
[0136] Another embodiment of compounds of Formula I includes any
one or more or combination of the following configurations for W:
18
[0137] Another group of compounds of Formula I includes compounds
where W.sup.1 is O. Another group of compounds of Formula I
includes compounds where W.sup.1 is S. Another group of compounds
of Formula I includes compounds where W.sup.5 and W.sup.6 are
independently H or a bond. Another group of compounds of Formula I
includes compounds where W.sup.1 is N(R.sub.15). Another group of
compounds of Formula I includes compounds where R.sub.15 is
independently any one of the following: H, alkyl, halogenated
alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl,
substituted cycloalkyl, heterocycloalkyl, halogenated
heterocycloalkyl, or substituted heterocycloalkyl, including, but
not limited to, lower alkyl, lower halogenated alkyl, or lower
substituted alkyl. Surprisingly, compounds where W is attached at
the five or six position have superior activity in the assays
discussed herein compared to the other regioisomers. Another group
of compounds of Formula I includes compounds where W is any one or
more of the following: 5-benzofuranyl, 6-benzofuranyl,
5-1H-indolyl, 6-1H-indolyl, 5-benzothienyl, or 6-benzothienyl, any
of which is optionally substituted at the carbon two or three
position with any one of the following: lower alkyl, including but
not limited to, methyl, ethyl, or isopropyl; lower halogenated
alkyl including, but not limited to, trifluoromethyl,
1,1,1-trifluoroethyl, or 1,1,1-trifluoro-2,2-difluoroethyl; lower
alkynyl including, but not limited to, ethynyl, or propyn-1-yl;
halogen; cyano; aminocarbonyl; formyl; or acetyl. Surprisingly, we
have found that the compounds having W be benzofuranyl have better
residence time in the brain and offer other benefits. Furthermore,
the bond from the carbonyl of the amide moiety should be attached
to W at carbon five or six of the W moiety. Another group of
compounds of Formula I includes compounds where W is 5-benzofuranyl
or 6-benzofuranyl, any of which is optionally substituted at the
carbon two or three position with any one of the following: lower
alkyl, including but not limited to, methyl, ethyl, or isopropyl;
lower halogenated alkyl including, but not limited to,
trifluoromethyl, 1,1,1-trifluoroethyl, or
1,1,1-trifluoro-2,2-difluoroeth- yl; lower alkynyl including, but
not limited to, ethynyl, or propyn-1-yl; halogen; cyano;
aminocarbonyl; formyl; or acetyl.
[0138] Another group of compounds of Formula I includes compounds
where R.sub.1 is H. Another group of compounds of Formula I
includes compounds where R.sub.1 is any one of the following:
alkyl, lower alkyl, halogenated alkyl, lower halogenated alkyl,
cycloalkyl, substituted phenyl, or substituted naphthyl, including
but not limited to, methyl, benzyl and the like.
[0139] Another group of compounds of Formula I includes compounds
where R.sub.2 is H. Another group of compounds of Formula I
includes compounds where R.sub.2 includes any one of the following:
F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, or aryl. Another group of compounds of Formula I
includes compounds where R.sub.2 includes any one of alkyl,
halogenated alkyl, substituted alkyl, cycloalkyl, or aryl,
including, but not limited to, lower alkyl including methyl, lower
halogenated alkyl, or lower substituted alkyl.
[0140] Another group of compounds of Formula I includes compounds
where R.sub.3 is H. Another group of compounds of Formula I
includes compounds where R.sub.3 is any one of the following: lower
alkyl, lower substituted alkyl, or lower halogenated alkyl.
[0141] Another group of compounds of Formula I includes compounds
where each R.sub.4 is H. Another group of compounds of Formula I
includes compounds where each R.sub.4 independently includes any
one of the following: H, F, Cl, Br, I, alkyl, lower alkyl,
halogenated alkyl, lower halogenated alkyl, substituted alkyl,
alkenyl, halogenated alkenyl, substituted alkenyl, alkynyl, lower
alkynyl, halogenated alkynyl, substituted alkynyl, cycloalkyl,
halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
halogenated heterocyloalkyl, substituted heterocycloalkyl, lactam
heterocylcoalkyl, phenyl, substituted phenyl, aminocarbonyl,
formyl, or acetyl, --OR.sub.10, --SR.sub.10, --SOR.sub.10,
--SO.sub.2R.sub.10, --NR.sub.10C(O)R.sub.5, --NR.sub.10C(O)R.sub.6,
--NR.sub.10C(O)R.sub.8, --NR.sub.10C(O)R.sub.10,
--N(R.sub.10).sub.2, --NO.sub.2, --C(O)R.sub.10, --CN,
--C(O).sub.2R.sub.10, --C(O)NHR.sub.10, --SCN,
--S(O)N(R.sub.10).sub.2, --S(O).sub.2NR.sub.10R.sub.10,
--NR.sub.10S(O).sub.2R.sub.10, R.sub.5, or R.sub.6. When R.sub.4 is
--SOR.sub.10, --COR.sub.10, --SO.sub.2R.sub.10, or
--CO.sub.2R.sub.10 and R.sub.10 is heterocycle, halogenated
heterocycle or heterocycle substituted with 1 substitutent selected
from R.sub.13, a carbon with sufficient valency in the heterocycle
is bonded to the carbon or sulfur; for example, but not limitation,
if R.sub.4 were pyrrolidinylcarbonyl, it would not be
pyrrolidin-1-ylcarbonyl because the carbonyl would be attached to
an atom other than carbon.
[0142] Another group of compounds of Formula I includes compounds
where each R.sub.8 is independently any one of the following: H,
alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,
halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
halogenated heterocycloalkyl, substituted heterocycloalkyl, phenyl,
or phenyl substituted with 0-4 independently selected from F, Cl,
Br, I, or R.sub.9.
[0143] Another group of compounds of Formula I includes compounds
where each R.sub.10 is independently any one of the following: 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.
[0144] Another group of compounds of Formula I includes compounds
where each R.sub.14 is independently any one of the following: H,
alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated
cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,
substituted cycloalkyl, substituted heterocycloalkyl, --OR.sub.11,
--SR.sub.11, --N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, --NR.sub.11S(O).sub.2R.sub.11, F,
Cl, Br, I, or a bond. When R.sub.14 is a bond, the bond connects
the moiety being R.sub.5 to another moiety and does not make an
unsaturated bond within the R.sub.5 moiety. R.sub.14 would only be
a bond if no other carbon atom within R.sub.5 allows for the bond
between the R.sub.5 moiety and the other moiety to which it is
bonded.
[0145] One of ordinary skill in the art will recognize that where
alkyl, halogenated alkyl, substituted alkyl, alkenyl, halogenated
alkenyl, substituted alkenyl, alkynyl, halogenated alkynyl, or
substituted alkynyl is allowed, the following, respectively, are
also allowed: lower alkyl, lower halogenated alkyl, lower
substituted alkyl, lower alkenyl, lower halogenated alkenyl, lower
substituted alkenyl, lower alkynyl, lower halogenated alkynyl, or
lower substituted alkynyl.
[0146] Another group of compounds of Formula I includes any one or
more or any combination of the following in a smaller group of
compounds of the following as the free base or a pharmaceutically
acceptable salt thereof:
[0147]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;
[0148]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;
[0149]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carbox-
amide;
[0150]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carbox-
amide;
[0151]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxa-
mide;
[0152]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-5-carboxa-
mide;
[0153]
N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxami-
de;
[0154]
N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxami-
de;
[0155]
2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carbox-
amide;
[0156]
2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carbox-
amide;
[0157]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carbox-
amide;
[0158]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-5-carbox-
amide;
[0159]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carbox-
amide;
[0160]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carbox-
amide;
[0161]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-6-car-
boxamide;
[0162]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-car-
boxamide;
[0163]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carbox-
amide;
[0164]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-5-carbox-
amide;
[0165]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-6-carboxa-
mide;
[0166]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxa-
mide;
[0167]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-6-carbo-
xamide;
[0168]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carbo-
xamide;
[0169]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-c-
arboxamide;
[0170]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-c-
arboxamide;
[0171]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-6-carboxa-
mide;
[0172]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxa-
mide;
[0173]
N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,6-dicarboxami-
de;
[0174]
N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarboxami-
de;
[0175]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide-
;
[0176]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide-
;
[0177]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indole-6-carboxamide;
[0178]
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indole-5-carboxamide; any
of which is optionally substituted on the C-2 of quinuclidine with
methyl in the S configuration, for example but not limitation, to
give
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxami-
de.
[0179] Another group of compounds of Formula I includes any one or
more or any combination of the following in a smaller group of
compounds of the following as the free base or a pharmaceutically
acceptable salt thereof:
[0180]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamid-
e;
[0181]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamid-
e;
[0182]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-methyl-1-benzofuran-6-c-
arboxamide;
[0183]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-methyl-1-benzofuran-5-c-
arboxamide;
[0184]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-6-ca-
rboxamide;
[0185]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-5-ca-
rboxamide;
[0186]
N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,6-dicarb-
oxamide;
[0187]
N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,5-dicarb-
oxamide;
[0188]
2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-c-
arboxamide;
[0189]
2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-c-
arboxamide;
[0190]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl-1-benzofuran-6-c-
arboxamide;
[0191]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl-1-benzofuran-5-c-
arboxamide;
[0192]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-methyl-1-benzofuran-6-c-
arboxamide;
[0193]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-methyl-1-benzofuran-5-c-
arboxamide;
[0194]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran--
6-carboxamide;
[0195]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran--
5-carboxamide;
[0196]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-6-c-
arboxamide;
[0197]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-5-c-
arboxamide;
[0198]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-6-ca-
rboxamide;
[0199]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-5-ca-
rboxamide;
[0200]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-benzofuran-6--
carboxamide;
[0201]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-benzofuran-5--
carboxamide;
[0202]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynyl-1-benzofura-
n-6-carboxamide;
[0203]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynyl-1-benzofura-
n-5-carboxamide;
[0204]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-6-ca-
rboxamide;
[0205]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-5-ca-
rboxamide;
[0206]
N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,6-dicarb-
oxamide;
[0207]
N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,5-dicarb-
oxamide;
[0208]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-6-carbox-
amide;
[0209]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-5-carbox-
amide;
[0210]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide;
[0211]
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-5-carboxamide;
[0212]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;
[0213]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamide;
[0214]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1-benzofuran-6-car-
boxamide;
[0215]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1-benzofuran-5-car-
boxamide;
[0216]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-cyano-1-benzofuran-6-carb-
oxamide;
[0217] N-[(3R,5R)-1-azabicyclo[3.2.1
]oct-3-yl)]-2-cyano-1-benzofuran-5-ca- rboxamide;
[0218]
N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-2,6-dicarbox-
amide;
[0219]
N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-2,5-dicarbox-
amide;
[0220]
2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-car-
boxamide;
[0221]
2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-car-
boxamide;
[0222]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-6-car-
boxamide;
[0223]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-5-car-
boxamide;
[0224]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-6-car-
boxamide;
[0225]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-5-car-
boxamide;
[0226]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benzofuran-6--
carboxamide;
[0227]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benzofuran-5--
carboxamide;
[0228]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chloro-1-benzofuran-6-car-
boxamide;
[0229]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chloro-1-benzofuran-5-car-
boxamide;
[0230]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-bromo-1-benzofuran-6-carb-
oxamide;
[0231]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-bromo-1-benzofuran-5-carb-
oxamide;
[0232]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-ethynyl-1-benzofuran-6-ca-
rboxamide;
[0233]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-ethynyl-1-benzofuran-5-ca-
rboxamide;
[0234]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran--
6-carboxamide;
[0235]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran--
5-carboxamide;
[0236]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-6-carb-
oxamide;
[0237]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-5-carb-
oxamide;
[0238]
N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,6-dicarbox-
amide;
[0239]
N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,5-dicarbox-
amide;
[0240]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-6-carboxam-
ide;
[0241]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-5-carboxam-
ide;
[0242]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-6-carboxamide;
[0243]
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-5-carboxamide;
[0244]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;
[0245]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;
[0246]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-6-carbox-
amide;
[0247]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-5-carbox-
amide;
[0248]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-6-carboxa-
mide;
[0249]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-5-carboxa-
mide;
[0250]
N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,6-dicarboxami-
de;
[0251]
N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,5-dicarboxami-
de;
[0252]
2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carbox-
amide;
[0253]
2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carbox-
amide;
[0254]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-6-carbox-
amide;
[0255]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-5-carbox-
amide;
[0256]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-6-carbox-
amide;
[0257]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-5-carbox-
amide;
[0258]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-6-car-
boxamide;
[0259]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-5-car-
boxamide;
[0260]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-6-carbox-
amide;
[0261]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-5-carbox-
amide;
[0262]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-6-carboxa-
mide;
[0263]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-5-carboxa-
mide;
[0264]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-6-carbo-
xamide;
[0265]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-5-carbo-
xamide;
[0266]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-6-c-
arboxamide;
[0267]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-5-c-
arboxamide;
[0268]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-6-carboxa-
mide;
[0269]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-5-carboxa-
mide;
[0270]
N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,6-dicarboxami-
de;
[0271]
N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,5-dicarboxami-
de;
[0272]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-6-carboxamide-
;
[0273]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-5-carboxamide-
;
[0274]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-6-carboxamide;
[0275]
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-5-carboxamide;
[0276]
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;
[0277]
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;
[0278]
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-6-carboxamid-
e;
[0279]
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-5-carboxamid-
e;
[0280]
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-6-carboxamide-
;
[0281]
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-5-carboxamide-
;
[0282]
N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,6-dicarboxamide;
[0283]
N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,5-dicarboxamide;
[0284]
2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamid-
e;
[0285]
2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamid-
e;
[0286]
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-6-carboxamid-
e;
[0287]
N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-5-carboxamid-
e;
[0288]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-6-carboxamid-
e;
[0289]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-5-carboxamid-
e;
[0290]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-6-carboxa-
mide;
[0291]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-5-carboxa-
mide;
[0292]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-6-carboxamid-
e;
[0293]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-5-carboxamid-
e;
[0294]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-6-carboxamide-
;
[0295]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-5-carboxamide-
;
[0296]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-6-carboxami-
de;
[0297]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-5-carboxami-
de;
[0298]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-6-carbo-
xamide;
[0299]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-5-carbo-
xamide;
[0300]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-6-carboxamide-
;
[0301]
N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-5-carboxamide-
;
[0302]
N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,6-dicarboxamide;
[0303]
N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,5-dicarboxamide;
[0304]
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-6-carboxamide;
[0305]
N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-5-carboxamide;
[0306]
N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-indole-6-carboxamide;
[0307]
N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-indole-5-carboxamide;
[0308]
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;
[0309]
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;
[0310]
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-6-carboxamid-
e;
[0311]
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-5-carboxamid-
e;
[0312]
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-6-carboxamide-
;
[0313]
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-5-carboxamide-
;
[0314]
N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,6-dicarboxamide;
[0315]
N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,5-dicarboxamide;
[0316]
2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamid-
e;
[0317]
2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamid-
e;
[0318]
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl-1-benzofuran-6-carboxamid-
e;
[0319]
N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl-1-benzofuran-5-carboxamid-
e;
[0320]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-6-carboxamid-
e;
[0321]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-5-carboxamid-
e;
[0322]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-6-carboxa-
mide;
[0323]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-5-carboxa-
mide;
[0324]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-6-carboxamid-
e;
[0325]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-5-carboxamid-
e;
[0326]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-6-carboxamide-
;
[0327]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-5-carboxamide-
;
[0328]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-6-carboxami-
de;
[0329]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-5-carboxami-
de;
[0330]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-6-carbo-
xamide;
[0331]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-5-carbo-
xamide;
[0332]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-6-carboxamide-
;
[0333]
N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-5-carboxamide-
;
[0334]
N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,6-dicarboxamide;
[0335]
N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,5-dicarboxamide;
[0336]
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-6-carboxamide;
[0337]
N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-5-carboxamide;
[0338] N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-indole-6-carboxamide;
or
[0339]
N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-indole-5-carboxamide.
[0340] The invention also concerns the synthesis of and isolation
of stereospecific intermediates and final compounds. Specifically,
the present invention concerns the stereospecific synthesis of
(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine, or salts thereof.
Although there are known procedures for making
1-azabicyclo[3.2.1]octan-3-amine, separation of the different
stereoismers as described herein occurs without using a chiral HPLC
separation procedure. The procedure within this invention results
in an efficient selective synthesis of
(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine.
[0341] Another aspect of the present invention includes a method
for making (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salt
thereof. One process for producing
(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or a salt thereof, from
(3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate, comprises:
the process of producing (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-a-
zoniabicyclo[3.2.1]octane chloride from (3R)-methyl
1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;
[0342] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one
or a salt thereof from
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1- ]octane
chloride;
[0343] and the process of producing
(3R,5R)-1-azabicyclo[3.2.1]octan-3-ami- ne or a salt thereof from
(5R)-1-azabicyclo[3.2.1]octan-3-one or a salt thereof.
[0344] Another process comprises: the process of producing
(3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from
(3R)-1-[(S)-1-phenethyl]-- 3-(cyanomethyl)pyrrolidine;
[0345] the process of producing
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azonia- bicyclo[3.2.1]octane
chloride from (3R)-methyl 1-[(S)-1-phenylethyl]pyrrol-
idine-3-acetate;
[0346] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one
or a salt thereof from
(5R)-3-oxo-1-[(IS)-1-phenylethyl]-1-azoniabicyclo[3.2.1- ]octane
chloride;
[0347] and the process of producing
(3R,5R)-1-azabicyclo[3.2.1]octan-3-ami- ne or a salt thereof from
(5R)-1-azabicyclo[3.2.1]octan-3-one or a salt thereof.
[0348] Another process comprises: the process of producing
(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from
(S)-(-)-.alpha.-methyl benzylamine;
[0349] the process of isolating
(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidi- ne-carboxylic acid from
a racemic mixture using a precipitating solvent without causing the
precipitation of other isomers, where the solvent can include a
primary alcohol, including but not limited to methanol;
[0350] the process of producing
(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)- pyrrolidine from
(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid;
[0351] the process of producing
(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)p- yrrolidine from
(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine;
[0352] the process of producing
(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)py- rrolidine from
(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine;
[0353] the process of producing (3R)-methyl
1-[(S)-1-phenylethyl]pyrrolidi- ne-3-acetate from
(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;
[0354] the process of producing
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azonia- bicyclo[3.2.1]octane
chloride from (3R)-methyl 1-[(S)-1-phenylethyl]pyrrol-
idine-3-acetate;
[0355] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one
or salt thereof from
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1- ]octane
chloride;
[0356] and the process of producing
(3R,5R)-1-azabicyclo[3.2.1]octan-3-ami- ne or salt thereof from
(5R)-1-azabicyclo[3.2.1]octan-3-one or salt thereof.
[0357] Another process comprises: the process of producing
(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from
(S)-(-)-.alpha.-methyl benzylamine;
[0358] the process of producing
(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)- pyrrolidine from
(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid;
[0359] the process of producing
(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)p- yrrolidine from
(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine;
[0360] the process of producing
(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)py- rrolidine from
(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine;
[0361] the process of producing (3R)-methyl
1-[(S)-1-phenylethyl]pyrrolidi- ne-3-acetate from
(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;
[0362] the process of producing
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azonia- bicyclo[3.2.1]octane
chloride from (3R)-methyl 1-[(S)-1-phenylethyl]pyrrol-
idine-3-acetate;
[0363] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one
or salt thereof from
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1 octane
chloride;
[0364] and the process of producing
(3R,5R)-1-azabicyclo[3.2.1]octan-3-ami- ne or salt thereof from
(5R)-1-azabicyclo[3.2.1]octan-3-one or salt thereof.
[0365] The present invention also includes the compounds of the
present invention, pharmaceutical compositions containing the
active compounds, and methods to treat the identified diseases.
[0366] Further aspects and embodiments of the invention may become
apparent to those skilled in the art from a review of the following
detailed description, taken in conjunction with the examples and
the appended claims. While the invention is susceptible of
embodiments in various forms, described hereafter are specific
embodiments of the invention with the understanding that the
present disclosure is intended as illustrative, and is not intended
to limit the invention to the specific embodiments described
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0367] Surprisingly, we have found that compounds of Formula I:
19
[0368] wherein Azabicyclo is 20
[0369] R.sub.1 is H, alkyl, halogenated alkyl, cycloalkyl,
substituted phenyl, or substituted naphthyl;
[0370] R.sub.2 is H, F, Cl, Br, I, alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, or aryl;
[0371] k is 1 or 2, provided that when k is 2, each R.sub.2 is
other than H;
[0372] R.sub.3 is H, lower alkyl, lower substituted alkyl, or lower
halogenated alkyl;
[0373] W.sup.1 is O, S, or N(R.sub.15);
[0374] W.sup.5 and W.sup.6 are independently H or a bond to the
carbonyl of Formula I, provided that only one of W.sup.5 and
W.sup.6 is said bond and the other is H;
[0375] Each R.sub.4 is independently H, F, Cl, Br, I, alkyl,
halogenated alkyl, substituted alkyl, alkenyl, halogenated alkenyl,
substituted alkenyl, alkynyl, halogenated alkynyl, substituted
alkynyl, cycloalkyl, halogenated cycloalkyl, substituted
cycloalkyl, heterocycloalkyl, halogenated heterocyloalkyl,
substituted heterocycloalkyl, lactam heterocylcoalkyl, phenyl,
substituted phenyl, --OR.sub.10, --SR.sub.10, --SOR.sub.10,
--SO.sub.2R.sub.10, --NR.sub.10C(O)R.sub.5, --NR.sub.10C(O)R.sub.6,
--NR.sub.10C(O)R.sub.8, --NR.sub.10C(O)R.sub.10,
--N(R.sub.10).sub.2, --NO.sub.2, --C(O)R.sub.10, --CN,
--C(O).sub.2R.sub.10, --C(O)NHR.sub.10, --SCN, --S(O)NHR.sub.10,
--S(O).sub.2NHR.sub.10, --NR.sub.10S(O).sub.2R.sub.10, R.sub.5, or
R.sub.6, provided that when R.sub.4 is --SO.sub.1-2R.sub.10 or
--CO.sub.1-2R.sub.10 and R.sub.10 is heterocycle, halogenated
heterocycle or heterocycle substituted with 1 substitutent selected
from R.sub.13, a carbon in the heterocycle is bonded to the carbon
or sulfur;
[0376] m is 1 or 2, provided that when m is 2 each R.sub.4 is other
than H;
[0377] R.sub.5 is a 5-membered heteroaromatic mono-cyclic moiety
containing within the ring 1-3 heteroatoms independently selected
from the group consisting of --O--, .dbd.N--, --N(R.sub.16)--, and
--S--, and having 0-1 substituent selected from R.sub.9, and
further having 0-3 substituents independently selected from F, Cl,
Br, or I,
[0378] or R.sub.5 is a 9-membered fused-ring moiety having a
6-membered ring fused to a 5-membered ring and having the formula
21
[0379] wherein each A is independently CR.sub.14 or N, provided
that only up to one A is N, E.sup.1 and E.sup.2 are independently
selected from CR.sub.14, O, S, or NR.sub.16, and G is CR.sub.14,
provided that R.sub.14 or R.sub.16 can be a bond when--forms a
double bond and further provided that only one R.sub.14 or R.sub.16
can be a bond for bonding R.sub.5 to a moiety to which it is
attached;
[0380] R.sub.6 is a 6-membered heteroaromatic mono-cyclic moiety
containing within the ring 1-3 heteroatoms selected from .dbd.N--
and having 0-1 substituent selected from R.sub.9 and 0-3
substituent(s) independently selected from F, Cl, Br, or I,
[0381] or R.sub.6 is a 10-membered heteroaromatic bi-cyclic moiety
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.9, and 0-3 substituent(s)
independently selected from F, Cl, Br, or I;
[0382] R.sub.7 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl,
or phenyl having 0-4 substituents independently selected from F,
Cl, Br, I, and R.sub.9;
[0383] Each R.sub.8 is independently H, alkyl, halogenated alkyl,
substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted
cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,
substituted heterocycloalkyl, phenyl, or phenyl substituted with
0-4 independently selected from F, Cl, Br, I, or R.sub.9;
[0384] R.sub.9 is alkyl, substituted alkyl, halogenated alky,
--OR.sub.11, --CN, --NO.sub.2, --NR.sub.10R.sub.10;
[0385] 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;
[0386] Each R.sub.11 is independently H, alkyl, cycloalkyl,
heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or
halogenated heterocycloalkyl;
[0387] 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, --N(R.sub.11).sub.2,
--C(O)R.sub.11, --NO.sub.2, --C(O)N(R.sub.11).sub.2, --CN,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2, or
--NR.sub.11S(O).sub.2R.sub.11;
[0388] R.sub.13 is --OR.sub.11, --SR.sub.11, --N(R.sub.11).sub.2,
--C(O)R.sub.11, --SOR.sub.11, --SO.sub.2R.sub.11,
--C(O)NR.sub.11R.sub.11- , --CN, --CF.sub.3,
--NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2- ,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2;
[0389] Each R.sub.14 is independently bond, H, alkyl, cycloalkyl,
heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,
halogenated heterocycloalkyl, substituted alkyl, substituted
cycloalkyl, substituted heterocycloalkyl, --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, --NR.sub.11S(O).sub.2, R.sub.11, F,
Cl, Br, I, or a bond, 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,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --NO.sub.2,
--C(O)N(R.sub.11).sub.2, --CN, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11).sub.2, 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;
[0390] R.sub.15 is H, alkyl, halogenated alkyl, substituted alkyl,
cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, halogenated heterocycloalkyl, or substituted
heterocycloalkyl;
[0391] Each R.sub.16 is indpendently bond, H, alkyl, halogenated
alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl,
substituted cycloalkyl, heterocycloalkyl, halogenated
heterocycloalkyl, or substituted heterocycloalkyl;
[0392] Aryl is phenyl, substituted phenyl, naphthyl, or substituted
naphthyl;
[0393] 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;
[0394] 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;
[0395] Alkyl is both straight- and branched-chain moieties having
from 1-6 carbon atoms;
[0396] Lower alkyl is both straight- and branched-chain moieties
having from 1-4 carbon atoms;
[0397] 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;
[0398] Lower halogenated alkyl is an alkyl moiety having from 1-4
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;
[0399] Substituted alkyl is an alkyl moiety from 1-6 carbon atoms
and having 0-3 substituents independently selected from R.sub.5,
R.sub.6, F, Cl, Br, or I 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- , --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, phenyl, or phenyl having 1 substituent selected from
R.sub.9 and further having 0-3 substituents independently selected
from F, Cl, Br, or I;
[0400] Lower substituted alkyl is lower alkyl having 0-3
substituents independently selected from F, Cl, Br, or I, and
further having 1 substituent selected from --OR.sub.10,
--SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2, --CN, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6,
[0401] wherein each R.sub.10 is independently H, lower alkyl,
cycloalkyl, heterocycloalkyl, or phenyl,
[0402] wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.11, or --NO.sub.2,
[0403] and wherein each R.sub.11 is independently H, lower alkyl,
lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl, lower
halogenated cycloalkyl, or halogenated heterocycloalkyl;
[0404] Alkenyl is straight- and branched-chain moieties having from
2-6 carbon atoms and having at least one carbon-carbon double
bond;
[0405] Lower alkenyl is straight- and branched-chain moieties
having from 2-4 carbon atoms and having at least one carbon-carbon
double bond;
[0406] 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;
[0407] Lower halogenated alkenyl is an unsaturated alkenyl moiety
having from 2-4 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;
[0408] 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 R.sub.5, R.sub.6, --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, phenyl, or phenyl having 1
substituent selected from R.sub.9, and further having 0-3
substituents independently selected from F, Cl, Br, or I;
[0409] Lower substituted alkenyl is lower alkenyl having 0-3
substituents independently selected from F, Cl, Br, or I, and
further having 1 substituent selected from R.sub.5, R.sub.6, --CN,
--OR.sub.10, --SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2- , --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6,
[0410] wherein each R.sub.10 is independently H, lower alkyl,
cycloalkyl, heterocycloalkyl, or phenyl,
[0411] wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.11, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.11, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11, --S(O).sub.2N(R.sub.11).sub.2,
--NR.sub.11S(O).sub.2R.sub.10, or --NO.sub.2,
[0412] and wherein each R.sub.11 is independently H, lower alkyl,
lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl, lower
halogenated cycloalkyl, or halogenated heterocycloalkyl;
[0413] Alkynyl is straight- and branched-chained moieties having
from 2-6 carbon atoms and having at least one carbon-carbon triple
bond;
[0414] Lower alkynyl is straight- and branched-chained moieties
having from 2-6 carbon atoms and having at least one carbon-carbon
triple bond;
[0415] 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;
[0416] Lower halogenated alkynyl is an unsaturated alkynyl moiety
having from 3-4 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;
[0417] 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 R.sub.5, R.sub.6, --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, phenyl, or phenyl having 1
substituent selected from R.sub.9, and further having 0-3
substituents independently selected from F, Cl, Br, or I;
[0418] Lower substituted alkynyl is lower alkynyl having 0-3
substituents independently selected from F, or Cl, and further
having 1 substituent selected from R.sub.5, R.sub.6, --OR.sub.10,
--SR.sub.10, --N(R.sub.10).sub.2, --C(O)R.sub.10,
--C(O)N(R.sub.10).sub.2, --CN, --NR.sub.10C(O)R.sub.10,
--S(O).sub.2N(R.sub.10).sub.2, --NR.sub.10S(O).sub.2R.sub.10,
--NO.sub.2, phenyl, R.sub.5, or R.sub.6,
[0419] wherein each R.sub.10 is independently H, lower alkyl,
cycloalkyl, heterocycloalkyl, or phenyl,
[0420] wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or
phenyl is optionally substituted with up to two halogens
independently selected from F or Cl and up to one other substituent
independently selected from --OR.sub.10, --SR.sub.11,
--N(R.sub.11).sub.2, --C(O)R.sub.10, --C(O)N(R.sub.11).sub.2, --CN,
--CF.sub.3, --NR.sub.11C(O)R.sub.11,
--S(O).sub.2N(R.sub.11,).sub.2, --NR.sub.11S(O).sub.2R.sub.11, or
--NO.sub.2,
[0421] and wherein each R.sub.11 is independently H, lower alkyl,
lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl, lower
halogenated cycloalkyl, or halogenated heterocycloalkyl;
[0422] Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon
atoms;
[0423] Halogenated cycloalkyl is a cyclic moiety having from 3-6
carbon atoms and having 1-4 substituents independently selected
from F, or Cl;
[0424] 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 phenyl having 1 substituent selected from
R.sub.9, and further having 0-3 substituents independently selected
from F, Cl, Br, or I;
[0425] Heterocycloalkyl is a cyclic moiety having 4-7 atoms with
1-2 atoms within the ring being --S--, --N(R.sub.7)--, or
--O--;
[0426] Halogenated heterocycloalkyl is a cyclic moiety having from
4-7 atoms with 1-2 atoms within the ring being --S--,
--N(R.sub.7)--, or --O--, and having 1-4 substituents independently
selected from F, or Cl;
[0427] Substituted heterocycloalkyl is a cyclic moiety having from
4-7 atoms with 1-2 atoms within the ring being --S--,
--N(R.sub.7)--, or --O-- and having 0-3 substituents independently
selected from --F, or --Cl, and further having 1 substituent
selected from R.sub.5, R.sub.6, --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.9 and further having 0-3
substituents independently selected from F, Cl, Br, or I;
[0428] 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.9
where valency allows;
[0429] 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.
[0430] 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.
[0431] The present invention also includes the intermediates, the
processes to make them and the active compounds of Formula I,
pharmaceutical compositions including the active compounds, and
methods to treat the identified diseases.
[0432] 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).
[0433] All temperatures are in degrees Centigrade.
[0434] Room temperature is within the range of 15-25 degrees
Celsius.
[0435] AChR refers to acetylcholine receptor.
[0436] nAChR refers to nicotinic acetylcholine receptor.
[0437] Pre-senile dementia is also known as mild cognitive
impairment.
[0438] 5HT.sub.3R refers to the serotonin-type 3 receptor.
[0439] .alpha.-btx refers to .alpha.-bungarotoxin.
[0440] 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).
[0441] TLC refers to thin-layer chromatography.
[0442] HPLC refers to high pressure liquid chromatography.
[0443] MeOH refers to methanol.
[0444] EtOH refers to ethanol.
[0445] IPA refers to isopropyl alcohol.
[0446] THF refers to tetrahydrofuran.
[0447] DMSO refers to dimethylsulfoxide.
[0448] DMF refers to N,N-dimethylformamide.
[0449] EtOAc refers to ethyl acetate.
[0450] TMS refers to tetramethylsilane.
[0451] TEA refers to triethylamine.
[0452] DIEA refers to N,N-diisopropylethylamine.
[0453] DIA refers to diisopropylamine.
[0454] MLA refers to methyllycaconitine.
[0455] Ether refers to diethyl ether.
[0456] HATU refers to
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluron- ium
hexafluorophosphate.
[0457] DBU refers to 1,8-diazobicyclo[5.4.0]undec-7-one.
[0458] CDI refers to carbonyl diimidazole.
[0459] NMO refers to N-methylmorpholine-N-oxide.
[0460] TPAP refers to tetrapropylammonium perruthenate.
[0461] Halogen is F, Cl, Br, or I.
[0462] Na.sub.2SO.sub.4 refers to sodium sulfate.
[0463] K.sub.2CO.sub.3 refers to potassium carbonate.
[0464] MgSO.sub.4 refers to magnesium sulfate.
[0465] When Na.sub.2SO.sub.4, K.sub.2CO.sub.3, or MgSO.sub.4 is
used as a drying agent, it is anhydrous.
[0466] 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.
[0467] Non-inclusive examples of heteroaryl compounds that fall
within the definition of R.sub.5 and R.sub.6 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.
[0468] Non-inclusive examples of heterocycloalkyl include, but are
not limited to, tetrahydrofurano, tetrahydropyrano, morpholino,
pyrrolidino, piperidino, piperazine, azetidino, azetidinono,
oxindolo, dihydroimidazolo, and pyrrolidinono
[0469] Mammal denotes human and other mammals.
[0470] Brine refers to an aqueous saturated sodium chloride
solution.
[0471] Equ means molar equivalents.
[0472] IR refers to infrared spectroscopy.
[0473] Lv refers to leaving groups within a molecule, including Cl,
OH, or mixed anhydride.
[0474] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (.delta.)
downfield from TMS.
[0475] 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 an ion
composed of the parent plus a proton. [M-H].sup.- refers to an ion
composed of the parent minus a proton. [M+Na].sup.+ refers to an
ion composed of the parent plus a sodium ion. [M+K].sup.+ refers to
an ion composed of the parent plus a potassium ion. EI refers to
electron impact. ESI refers to electrospray ionization. CI refers
to chemical ionization. FAB refers to fast atom bombardment.
[0476] Amino protecting group includes, but is not limited to,
carbobenzyloxy (CBz), tert butoxy carbonyl (BOC) and the like.
Examples of other suitable amino protecting groups are known to
person skilled in the art and can be found in "Protective Groups in
Organic synthesis," 3rd Edition, authored by Theodora Greene and
Peter Wuts.
[0477] 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.
[0478] 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.
[0479] 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.
[0480] 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.
[0481] 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.
[0482] 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.
[0483] .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 (.alpha.-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.
[0484] 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, Mar. 1999; Wilens, T. E. et. al., Am. J.
Psychiatry, 156(12):1931-7, Dec. 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.
[0485] 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.
[0486] 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.
[0487] 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 a7/5-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.
[0488] 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.
[0489] 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.
[0490] 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.
[0491] 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.
[0492] 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.
[0493] 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.
[0494] 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.
[0495] A pharmaceutical combination therapy composition can include
therapeutically effective amounts of the compounds of Formula I 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.
[0496] 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.
[0497] 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.
[0498] 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.
[0499] 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.
[0500] 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.
[0501] 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.
[0502] 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 any one or more or combination of
the following: attention deficit disorder, attention deficit
hyperactivity disorder, depression, anxiety, general anxiety
disorder, post traumatic stress 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, Parkinson's disease, tardive
dyskinesia, Pick's disease, 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, age-related macular degeneration, glaucoma,
neurodegeneration associated with glaucoma, or symptoms associated
with pain.
[0503] 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.
[0504] 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.
[0505] 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.
[0506] Anxiety disorders (disorders with prominent anxiety or
phobic avoidance), represent an area of umet medical needs in the
treatment of psychiatric illness. See Diagnostic & Statistical
Manual of Mental Disorders, IV (1994), pp 393-394, for various
disease forms of anxiety.
[0507] 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.
[0508] Anxiety also includes post-traumatic stress disorder (PTSD),
which 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.
[0509] 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.
[0510] 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.
[0511] 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.
[0512] 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.
[0513] 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.
[0514] 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.
[0515] 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.
[0516] 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.
[0517] 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.
[0518] 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.
[0519] 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.
[0520] 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.
[0521] 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.
[0522] 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.
[0523] 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.
[0524] 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.
[0525] 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.
[0526] 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.
[0527] 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.
[0528] 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.
[0529] 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.
[0530] 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.
[0531] 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
eradicate 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.
[0532] Finally, the compounds of the present invention may be used
in combination therapy with typical and atypical anti-psychotic
drugs (also called an anti-psychotic agent). 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.
[0533] 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 an amino-azabicyclic moiety with the requisite acid
chloride (Lv=Cl), mixed anhydride (e.g., Lv=diphenyl phosphoryl,
bis(2-oxo-3-oxazolidinyl)p- hosphinyl, 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=OH) in the presence of an
activating agent. Suitable activating regents 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).
Scheme 1
Lv-C(O--W+Azabicyclo-NH.sub.2.fwdarw.Azabicyclo-N(H)--C(O)--W
[0534] Generally, the acid is activated using HATU or is converted
to the acyl azide by using DPPA or is converted into a mixed
anhydride by treatment with bis (2-oxo-3-oxazolidinyl) phosphinic
chloride in the presence of TEA with CH.sub.2Cl.sub.2 or CHCl.sub.3
as the solvent; the resulting anhydride solution is directly
reacted with the appropriate Azabicyclo moiety added neat or using
DMF or aqueous DMF as solvent. In some cases, the ester (Lv being
OMe or OEt) may be reacted directly with the amine in refluxing
methanol or ethanol to give the compounds of Formula I.
[0535] The appropriate amine is treated with TEA if the amine is in
the form of an acid salt and added to a solution of the appropriate
anhydride or azide to give the desired final compounds. In some
cases, the ester (Lv being OMe or OEt) may be reacted directly with
the amine in refluxing methanol or ethanol to give the compounds of
Formula I.
[0536] One of ordinary skill in the art will recognize that the
methods described for the reaction of the unsubstituted
3-aminoquinuclidine (R.sub.2 is H) are equally applicable to
substituted compounds (R.sub.2 is other than H). Certain
6-substituted-[2.2.2]-3-amines (Azabicyclo I) are known in the art.
The preparation of compounds where R.sub.2 is at C-6 of the
quinuclidine and is other than H is described in Acta Pol. Pharm.
1981, 179. Certain 2-substituted-[2.2.2]-3-amines (Azabicyclo I)
are known in the art. The preparation of compounds where R.sub.2 is
at C-2 of the quinuclidine and is other than H is described in J.
Med. Chem. 1975, 18, 587.
[0537] Alternatively, there are several methods to obtain the amine
precursor for Azabicyclo I where R.sub.2 is other than H. Although
the scheme depicted below is for compounds where R.sub.2 is at the
C-6 position of the quinuclidine, one of ordinary skill in the art
would be able to obtain the quinuclidine with substitution at C-2
also. The substituted-[2.2.2]-3-amine can be prepared by reduction
of an oxime or an imine of the corresponding
substituted-3-quinuclidinone by methods known to one of ordinary
skill in the art (see J. Labelled Compds. Radiopharm. 1995, 53; J.
Med. Chem. 1998, 988; Synth. Commun. 1992, 1895; Synth. Commun.
1996, 2009). Alternatively, the substituted-[2.2.2]-3-amin- e can
be prepared from a substituted-3-hydroxyquinuclidine by Mitsunobu
reaction followed by deprotection as described in Synth. Commun.
1995, 1895. Alternatively, the substituted-[2.2.2]-3-amine can be
prepared by conversion of a substituted-3-hydroxyquinuclidine into
the corresponding mesylate or tosylate, followed by displacement
with sodium azide and reduction as described in J. Med. Chem. 1975,
587. 22
[0538] The 2-substituted-3-quinuclidinones, where R.sub.2 is
substituted alkyl or cycloalkyl, can be prepared by known
procedures (see Tet. Lett. 1972, 1015; J. Am. Chem. Soc. 1994,
1278; J. Am. Chem. Soc. 1989, 4548; Tetrahedron, 2000, 1139). The
2-substituted-3-quinuclidinones, where R.sub.2 is aryl, can be
prepared by palladium catalyzed arylation as described in J. Am.
Chem. Soc. 1999, 1473 and J. Am. Chem. Soc. 2000, 1360. The
6-substituted-3-quinuclidinones can be prepared by known procedures
(see J. Gen. Chem. Russia 1963, 3791, J. Chem. Soc. Perkin Trans. I
1991, 409, J. Org. Chem. 2000, 3982).
[0539] One of ordinary skill in the art will recognize that the
methods described for the reaction of the unsubstituted
3-amino-1-azabicyclo[2.2.- 1]heptane (R.sub.2.dbd.H) are equally
applicable to substituted compounds (R.sub.2.noteq.H). For where
Azabicyclo II has substitution at C-2, compounds can be prepared
from appropriately substituted nitro alcohols using procedures
described in Tetrahedron 1997, 53, p. 11121 as shown below. Methods
to synthesize nitro alcohols are well known in the art (see J. Am.
Chem. Soc. 1947, 69, p 2608). The scheme below is a modification of
the synthesis of exo-3-amino-1-azabicyclo[2.2.1]heptane as the
bis(hydro para-toluenesulfonate) salt, described in detail herein,
to show how to obtain these amine precursors. The desired salt can
be made using standard procedures. 23
[0540] For Azabicyclo II where R.sub.2 is other than H at the C-6
position, compounds can also be prepared by modification of
intermediates described in the synthesis of
exo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydro
para-toluenesulfonate) salt, described in detail herein. For
example, Int 6 can be oxidized to the aldehyde and treated with an
organometallic reagent to provide Int 20 using procedures described
in Tetrahedron 1999, 55, p 13899. Int 20 can be converted into the
amine using methods described for the synthesis of
exo-3-amino-1-azabicyclo[2.2- .1]heptane as the bis(hydro
para-toluenesulfonate) salt. Once the amine is obtained, the
desired salt can be made using standard procedures. 24
[0541] The schemes used are for making
exo-3-amino-1-azabicyclo[2.2.1]hept- ane. However, the
modifications discussed are applicable to make the endo isomer
also.
[0542] One of ordinary skill in the art will also recognize that
the methods described for the reaction of the unsubstituted
1-azabicyclo[3.2.1]octan-3-amine or
1-azabicyclo[3.2.2]nonan-3-amine (R.sub.2.dbd.H) are equally
applicable to substituted compounds (R.sub.2.noteq.H). The R.sub.2
substituent may be introduced as known to one skilled in the art
through standard alkylation chemistry. Exposure of
1-azabicyclo[3.2.1]octan-3-one or 1-azabicyclo[3.2.2]nonan-3-one to
a hindered base such as LDA (lithium diisopropylamide) in a solvent
such as THF or ether between 0.degree. C. to -78.degree. C.
followed by the addition of an alkylating agent (R.sub.2Lv, where
Lv=Cl, Br, I, OTs, etc.) will, after being allowed to warm to about
0.degree. C. to rt followed by an aqueous workup, provide the
desired compound as a mixture of isomers. Chromatographic
resolution (flash, HPLC, or chiral HPLC) will provided the desired
purified alkylated ketones. From there, formation of the oxime and
subsequent reduction will provide the desired stereoisomers.
[0543] N-(2-azabicyclo[2.2.1]hept)-5-amine and 6-amine 25
[0544] where Lv can be --CH.sub.2Ph, --CH(Me)Ph, --OH, --OMe, or
--OCH.sub.2Ph.
[0545] The respective amine precursors for Azabicyclo V and
Azabicyclo VI can be prepared by reduction of an oxime or an imine
of the corresponding N-2-azabicyclo[2.2.1]-heptanone by methods
known to one skilled in the art (see J. Labelled Compds.
Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth.
Commun. 1895-1911 (1992), Synth. Commun. 2009-2015 (1996)). The
oximes can be prepared by treatment of the
N-2-azabicyclo[2.2.1]heptanones with hydroxylamine hydrochloride in
the presence of a base. The imines can be prepared by treatment of
the N-2-azabicyclo[2.2.1]-heptanones with a primary amine under
dehydrating conditions. The N-2-azabicyclo[2.2.1]heptanones can be
prepared by known procedures (see Tett. Lett. 1419-1422 (1999), J.
Med. Chem. 2184-2191 (1992), J. Med. Chem. 706-720 (2000), J. Org.
Chem., 4602-4616 (1995)).
[0546] 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.
Amines
Preparation of N-(2S,3R)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine
dihydrochloride (2S-methyl-2.2.2-Amine)
[0547] A mixture of 2-methylene-3-quinuclidinone dihydrate
hydrochloride (27.18 g, 0.1296 mol, 1 eq) and K.sub.2CO.sub.3 (86.0
g, 0.6213 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 17.8 g (100%) of
2-methylenequinuclidin-3-one as a yellow oil. MS (ESI) for
C.sub.8H.sub.11NO m/z 138.1 (M.sup.+).
[0548] 2-Methylenequinuclidin-3-one (17.8 g, 0.1296 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
16.2 g (90%) of 2-methylquinuclidin-3-one. MS (ESI) for
C.sub.8H.sub.13NO m/z 140.2 (M.sup.+).
[0549] 2-Methylquinuclidin-3-one (39.59 g, 0.2844 mol, 1 eq) and
hydroxylamine hydrochloride (20.0 g, 0.2878 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 (0.8 H), 1.57 (0.6 H),
1.47 (2.4 H).
[0550] 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 (2.sup.nd crop) and 1.5 g (3.sup.rd crop); this material is a
mixture of both trans and cis isomers.
[0551] 4-Chlorobenzoic acid (26.3 g, 0.1681 mol, 1.1 eq) and TEA
(106 mL, 0.764 mol, Seq.) are dissolved in 300 mL THF.
Diphenylphosphoryl chloride (32.0 mL, 0.1681 mol, 1.1 eq) is added
dropwise. After 1 h, trans 2-methylquinuclidin-3-amine
dihydrochloride (32.6 g, 0.1528 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=+3.de- gree. (c 0.96, methanol). HRMS (FAB)
calcd for C.sub.15H.sub.19ClN.sub.2O+- H 279.1264, found
279.1272.
[0552] A solution of
4-chloro-N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-
-yl]benzamide (17.2 g, 61.7 mmol) in absolute EtOH (70 mL) 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.+).
26
Step A. Preparation of 2-(benzoyloxy)-1-nitroethane (Int 1)
[0553] Benzoyl chloride (14.9 mL, 128 mmol) is added to a stirred
solution of nitroethanol (9.2 mL, 128 mmol) in dry benzene (120
mL). The solution is refluxed for 24 hr and then concentrated in
vacuo. The crude product is purified by flash chromatography on
silica gel. Elution with hexanes-EtOAc (80:20) affords Int I as a
white solid (68% yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.0, 7.6, 7.4, 4.9, 4.8.
Step B. Preparation of ethyl E-4-(benzylamino)-2-butenoate (Int
2)
[0554] Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is
added to a stirred solution of benzylamine (16 mL, 146 mmol) in
CH.sub.2Cl.sub.2 (200 mL) at rt. The reaction mixture stirs for 15
min, and is diluted with ether (1 L). The mixture is washed with
saturated aqueous NaHCO.sub.3 solution (3.times.) and water, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue is purified by flash chromatography on silica gel. Elution
with hexanes-EtOAc (70:30) affords Int 2 as a clear oil (62%
yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.4-7.2, 7.0,
6.0, 4.2, 3.8, 3.4, 2.1-1.8, 1.3.
Step C. Preparation of
trans-4-nitro-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester
(Int 3)
[0555] A solution of Int 1 (6.81 g, 34.9 mmol) and Int 2 (7.65 g,
34.9 mmol) in EtOH (70 mL) stirs at rt for 15 h and is then
concentrated in vacuo. The residue is diluted with ether (100 mL)
and saturated aqueous NaHCO.sub.3 solution (100 mL). The organic
layer is separated and dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude product is purified by flash
chromatography on silica gel. Elution with hexanes-EtOAc (85:15)
affords Int 3 as a clear oil (76% yield): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.4-7.3, 4.8-4.7, 4.1, 3.8-3.6, 3.3-3.0,
2.7-2.6, 2.4-2.3, 1.2.
Step D. Preparation of
trans-4-amino-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester
(Int 4)
[0556] A mixture of Int 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in
EtOH (100 mL) is placed in a Parr bottle and hydrogenated for 4 h
under an atmosphere of hydrogen (46 psi) at rt. The mixture is
filtered through a pad of Celite, and the solvent is removed in
vacuo to afford Int 4 as a clear oil (100% yield): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.3-7.2, 4.1, 3.6, 3.2, 3.0-2.9, 2.8,
2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.
Step E. Preparation of
trans-4-(1,1-dimethylethoxycarbonylamido)-1-(phenyl-
methyl)-3-pyrrolidineacetic acid ethyl ester (Int 5)
[0557] Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to a
stirred solution of Int 4 (2.94 g, 11.2 mmol) in CH.sub.2Cl.sub.2
(30 mL) cooled in an ice bath. The reaction is allowed to warm to
rt and stirred overnight. The mixture is concentrated in vacuo. The
crude product is purified by flash chromatography on silica gel.
Elution with hexanes-EtOAc (80:20) affords Int 5 as a white solid
(77% yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.4-7.2,
5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0, 2.8-2.6, 2.5-2.4, 2.3-2.1,
1.4, 1.3.
Step F. Preparation of trans
(tert-butoxycarbonylamino)-4-(2-hydroxyethyl)- -1-(N-phenylmethyl)
pyrrolidine (Int 6)
[0558] LiAlH.sub.4 powder (627 mg, 16.5 mmol) is added in small
portions to a stirred solution of Int 5 (3.0 g, 8.3 mmol) in
anhydrous THF (125 mL) in a -5.degree. C. bath. The mixture is
stirred for 20 min in a -5.degree. C. bath, then quenched by the
sequential addition of water (0.6 mL), 15% (w/v) aqueous NaOH (0.6
mL) and water (1.8 mL). Excess anhydrous K.sub.2CO.sub.3 is added,
and the mixture is stirred for 1 h, then filtered. The filtrate is
concentrated in vacuo. The residue is purified by flash
chromatography on silica gel. Elution with EtOAc affords Int 6 as a
white solid (94% yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7, 3.3-3.2, 2.8-2.7, 2.3-2.1, 1.7
1.5.
[0559] Int 6 is a racemic mixture that can be resolved via
chromatography using a Diacel chiral pack AD column. From the two
enantiomers thus obtained, the (+)-enantiomer,
[.alpha.].sup.25.sub.D+35 (c 1.0, MeOH), gives rise to the
corresponding enantiomerically pure exo-4-S final compounds,
whereas the (-)-enantiomer, [.alpha.].sup.25.sub.D34 (c 0.98,
MeOH), gives rise to enantiomerically pure exo-4-R final compounds.
The methods described herein use the (+)-enantiomer of Int 6 to
obtain the enantiomerically pure exo-4-S final compounds. However,
the methods used are equally applicable to the (-)-enantiomer of
Int 6, making non-critical changes to the methods provided herein
to obtain the enantiomerically pure exo-4-R final compounds.
Step G. Preparation of exo
3-(tert-butoxycarbonylamino)-1-azabicyclo[2.2.1- ]heptane (Int
7)
[0560] TEA (8.0 g, 78.9 mml) is added to a stirred solution of Int
6 (2.5 g, 7.8 mmol) in CH.sub.2Cl.sub.2 (50 mL), and the reaction
is cooled in an ice-water bath. CH.sub.3SO.sub.2Cl (5.5 g, 47.8
mmol) is then added dropwise, and the mixture is stirred for 10 min
in an ice-water bath. The resulting yellow mixture is diluted with
saturated aqueous NaHCO.sub.3 solution, extracted with
CH.sub.2Cl.sub.2 several times until no product remains in the
aqueous layer by TLC. The organic layers are combined, washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
residue is dissolved in EtOH (85 mL) and is heated to reflux for 16
h. The reaction mixture is allowed to cool to rt, transferred to a
Parr bottle and treated with 10% Pd/C catalyst (1.25 g). The bottle
is placed under an atmosphere of hydrogen (53 psi) for 16 h. The
mixture is filtered through Celite, and fresh catalyst (10% Pd/C,
1.25 g) is added. Hydrogenolysis continues overnight. The process
is repeated three more times until the hydrogenolysis is complete.
The final mixture is filtered through Celite and concentrated in
vacuo. The residue is purified by flash chromatography on silica
gel. Elution with CHCl.sub.3--MeOH--NH.sub- .4OH (90:9.5:0.5)
affords Int 7 as a white solid (46% yield): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 5.6-5.5, 3.8-3.7, 3.3-3.2, 2.8-2.7, 2.0-1.8,
1.7-1.5, 1.5.
Step H. Preparation of exo-3-amino-1-azabicyclo[2.2.1]heptane
bis(hydro-para-toluenesulfonate)
[0561] Para-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) is
added to a stirred solution of Int 7 (770 mg, 3.63 mmol) in EtOH
(50 mL). The reaction mixture is heated to reflux for 10 h,
followed by cooling to rt. The precipitate is collected by vacuum
filtration and washed with cold EtOH to give exo-[2.2.1]-Amine as a
white solid (84% yield): .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4, 2.3-2.2, 1.9-1.8.
[0562] Synthesis of endo-3-amino-1-azabicyclo[2.2.1]heptane as the
bis(hydro para-toluenesulfonate) salt (endo-[2.2.1]-Amine): 27
Step I. Preparation of ethyl
5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-- carboxylate (Int
10)
[0563] Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanically
stirred suspension of potassium ethoxide (33.2 g, 395 mmol) in dry
toluene (0.470 L). When the mixture is homogeneous, 2-pyrrolidinone
(33.6 g, 395 mmol) is added, and then a solution of diethyl oxalate
(53.1 mL, 390 mmol) in toluene (98 mL) is added via an addition
funnel. After complete addition, toluene (118 mL) and EtOH (78 mL)
are added sequentially. The mixture is heated to reflux for 18 h.
The mixture is cooled to rt and aqueous HCl (150 mL of a 6.0 M
solution) is added. The mixture is mechanically stirred for 15 min.
The aqueous layer is extracted with CH.sub.2Cl.sub.2, and the
combined organic layers are dried (MgSO.sub.4), filtered and
concentrated in vacuo to a yellow residue. The residue is
recrystallized from EtOAc to afford Int 10 as a yellow solid (38%
yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 11.4, 7.4, 4.3,
3.4, 2.6, 1.3.
Step J. Preparation of ethyl
cis-3-hydroxy-2-oxopiperidine-4-carboxylate (Int 11)
[0564] A mixture of Int 10 (15 g, 81 mmol) and 5% rhodium on carbon
(2.0 g) in glacial acetic acid is placed under an atmosphere of
hydrogen (52 psi). The mixture is shaken for 72 h. The mixture is
filtered through Celite, and the filtrate is concentrated in vacuo
to afford Int 11 as a white solid (98% yield): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 6.3, 4.2, 4.0-3.8, 3.4, 3.3-3.2, 2.2,
1.3.
Step K. Preparation of cis-4-(hydroxymethyl)piperidin-3-ol (Int
12)
[0565] Int 11 (3.7 g, 19.9 mmol) as a solid is added in small
portions to a stirred solution of LiAlH.sub.4 in THF (80 mL of a
1.0 M solution) in an ice-water bath. The mixture is warmed to rt,
and then the reaction is heated to reflux for 48 h. The mixture is
cooled in an ice-water bath before water (3.0 mL, 170 mmol) is
added dropwise, followed by the sequential addition of NaOH (3.0 mL
of a 15% (w/v) solution) and water (9.0 mL, 500 mmol). Excess
K.sub.2CO.sub.3 is added, and the mixture is stirred vigorously for
15 min. The mixture is filtered, and the filtrate is concentrated
in vacuo to afford Int 12 as a yellow powder (70% yield): .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. 4.3, 4.1, 3.7, 3.5-3.2,
2.9-2.7, 2.5-2.3, 1.5, 1.3.
Step L. Preparation of benzyl
cis-3-hydroxy-4-(hydroxymethyl)piperidine-1-- carboxylate (Int
13)
[0566] N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is
added to a stirred solution of Int 12 (1.6 g, 12.2 mmol) in
saturated aqueous NaHCO.sub.3 (15 mL) at rt. The mixture is stirred
at rt for 18 h. The organic and aqueous layers are separated. The
aqueous layer is extracted with ether (3.times.). The combined
organic layers are dried over anhydrous K.sub.2CO.sub.3, filtered
and concentrated in vacuo to afford Int 13 as a yellow oil (99%
yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.4-7.3, 5.2,
4.3, 4.1, 3.8-3.7, 3.0-2.8, 2.1, 1.9-1.7, 1.4.
Step M. Preparation of benzyl
cis-3-hydroxy-4-[(4-methylphenyl)sulfonyl
oxymethyl]piperidine-1-carboxylate (Int 14)
[0567] Para-toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to
a stirred solution of Int 13 (3.6 g, 5.3 mmol) in pyridine (10 mL)
in a -15.degree. C. bath. The mixture is stirred for 4 h, followed
by addition of HCl (4.5 mL of a 6.0 M solution). CH.sub.2Cl.sub.2
(5 mL) is added. The organic and aqueous layers are separated. The
aqueous layer is extracted with CH.sub.2Cl.sub.2. The combined
organic layers are washed with brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo to afford Int 14 as a colorless oil (78%
yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.8, 7.4-7.2,
5.1, 4.3-4.2, 4.1, 3.9-3.8, 2.9-2.7, 2.4, 1.9, 1.6-1.3.
Step N. Preparation of exo-1-azabicyclo[2.2.1]heptan-3-ol (Int
15)
[0568] A mixture of Int 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst
(500 mg) in EtOH (50 mL) is placed under an atmosphere of hydrogen.
The mixture is shaken for 16 h. The mixture is filtered through
Celite. Solid NaHCO.sub.3 (1.1 g, 13 mmol) is added to the
filtrate, and the mixture is heated in an oil bath at 50.degree. C.
for 5 h. The solvent is removed in vacuo. The residue is dissolved
in saturated aqueous K.sub.2CO.sub.3 solution. Continuous
extraction of the aqueous layer using a liquid-liquid extraction
apparatus (18 h), followed by drying the organic layer over
anhydrous K.sub.2CO.sub.3 and removal of the solvent in vacuo
affords Int 15 as a white solid (91% yield): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 3.8, 3.0-2.8, 2.6-2.5, 2.4-2.3, 1.7, 1.1.
Step O. Preparation of endo-3-azido-1-azabicyclo[2.2.1]heptane (Int
16)
[0569] To a mixture of Int 15 (1.0 g, 8.9 mmol) and triphenyl
phosphine (3.0 g, 11.5 mmol) in toluene-THF (50 mL, 3:2) in an
ice-water bath are added sequentially a solution of hydrazoic acid
in toluene (15 mL of ca. 2 M solution) and a solution of diethyl
azadicarboxylate (1.8 mL, 11.5 mmol) in toluene (20 mL). The
mixture is allowed to warm to rt and stir for 18 h. The mixture is
extracted with aqueous 1.0M HCl solution. The aqueous layer is
extracted with EtOAc, and the combined organic layers are
discarded. The pH of the aqueous layer is adjusted to 9 with 50%
aqueous NaOH solution. The aqueous layer is extracted with
CH.sub.2Cl.sub.2 (3.times.), and the combined organic layers are
washed with brine, dried over Na.sub.2SO.sub.4, 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 (92:7:1) affords Int 16 as a colorless
oil (41 % yield): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.1,
3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.
Step P. Preparation of endo-3-amino-1-azabicyclo[2.2.1]heptane
bis(hydro-para-toluenesulfonate)
[0570] A mixture of Int 16 (250 mg, 1.8 mmol) and 10% Pd/C catalyst
(12 mg) in EtOH (10 mL) is placed under an atmosphere of hydrogen
(15 psi). The mixture is stirred for 1 h at rt. The mixture is
filtered through Celite, and the filtrate is concentrated in vacuo.
The residue is dissolved in EtOH (10 mL) and para-toluenesulfonic
acid monohydrate (690 mg, 3.7 mmol) is added. The mixture is
stirred for 30 min, and the precipitate is filtered. The
precipitate is washed sequentially with cold EtOH and ether. The
precipitate is dried in vacuo to afford endo-[2.2.1]-Amine as a
white solid (85% yield): .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.7, 7.3, 4.2, 3.9, 3.6-3.4, 3.3-3.2, 2.4, 2.3, 2.1.
Preparation of 1-azabicyclo[3.2.1]octan-3-amine
Preparation of the 3R,5R-[3.2.1]-Amine
[0571] 28
(3S)-1-[(S)-1-Phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid
[0572] 29
[0573] According to the literature procedure (Nielsen et al. J.
Med. Chem 1990, 70-77), a mixture of itaconic acid (123.17 g, 946.7
mmol) and (S)-(-)-.alpha.-methyl benzylamine (122.0 mL, 946.4 mmol)
were heated (neat) in a 160.degree. C. oil bath for 4 h. Upon
cooling, MeOH (.about.200 mL) was added and the resulting solid
collected by filtration. The solid was treated with EtOH
(.about.700 mL) and warmed using a steam bath until .about.450 mL
solvent remained. After cooling to rt, the solid was collected and
dried to afford 83.2 g as a white crystalline solid:
[.alpha.].sup.25.sub.D=-80 (c 0.97, DMSO). MS (EI) m/z 233
(M.sup.+), 233, 218, 160, 105, 104, 103, 91, 79, 78, 77.
[0574] The lack of a resonance 3.59 indicates a single
diastereomer. The other diastereomer can be retrieved from the
initial MeOH triturant. Attempts to crystallize this material
generally led to small quantities of
(3RS)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid.
(3S)-1-[(S)-1-Phenethyl]-3-(hydroxymethyl)pyrrolidine
[0575] 30
[0576] A suspension
(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxyli- c acid
(82.30 g, 352.8 mmol) in Et.sub.2O (200 mL) was added in small
portions to a slurry of LiAlH.sub.4 (17.41 g, 458.6 mmol) in
Et.sub.2O (700 mL). The mixture began to reflux during the
addition. The addition funnel containing the suspension was rinsed
with Et.sub.2O (2.times.50 mL), and the mixture was heated in a
50.degree. C. oil bath for an additional 2 h and first allowed to
cool to rt and then further cooled using an ice bath. The mixture
was carefully treated with H.sub.2O (62 mL). The resulting
precipitate was filtered, rinsed with Et.sub.2O, and discarded. The
filtrate was concentrated to a yellow oil. When EtOAc was added to
the oil, a solid began to form. Hexane was then added and removed
by filtration and dried to afford 43.3 g as a white solid.
[.alpha.].sup.25.sub.D=-71 (c 0.94, CHCl.sub.3). MS (EI) m/z 205
(M.sup.+), 191, 190, 128, 105, 91, 86, 84, 79, 77, 51.
(3R)-1-[(S)-1-Phenethyl]-3-(cyanomethyl)pyrrolidine
[0577] 31
[0578] A solution of
(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine (42.75 g,
208.23 mmol) in chloroform (350 mL) was heated to reflux under
N.sub.2. The solution was treated with a solution of thionyl
chloride (41.8 mL, 573 mmol) in chloroform (40 mL) dropwise over 45
min. The mixture stirred for an additional 30 min, was cooled and
concentrated. The residue was diluted with H.sub.2O (-200 mL), 1 N
NaOH was added until a pH .about.8 (pH paper). A small portion
(.about.50 mL) of sat. NaHCO.sub.3 was added and the basic mixture
was extracted with EtOAc (3.times.400 mL), washed with brine, dried
(MgSO.sub.4), filtered and concentrated to give 46.51 g of a
red-orange oil for
(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine: R.sub.f: 0.50
(EtOAc-hexane 1:1); MS (ESI+) m/z 224.2 (MH.sup.+). The chloride
(46.35 g, 208.0 mmol) was transferred to a flask, dimethyl
sulfoxide (200 mL) was added, and the solution was treated with
NaCN (17.84 g, 363.9 mmol). The mixture was heated under N.sub.2 in
a 100.degree. C. oil bath overnight and was cooled. The brown
mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc
(1000 mL in portions). The combined organic layer was washed with
H.sub.2O (6.times..about.50 mL), brine (.about.100 mL), dried
(MgSO.sub.4), filtered and concentrated to give 40.61 g as an
orange-red oil: R.sub.f: 0.40 (EtOAc-PhCH.sub.3 1:1). MS (ESI+) for
m/z 215.2 (M+H.sup.+).
(3R)-Methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate
[0579] 32
[0580] Acetyl chloride (270 mL, 3.8 mol) was carefully added to a
flask containing chilled (0.degree. C.) methanol (1100 mL). After
the addition was complete, the acidic solution stirred for 45 min
(0.degree. C.) and then
(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine (40.50 g, 189.0
mmol) in methanol (200 mL) was added. The ice bath was removed and
the mixture stirred for 100 h at rt. The resulting suspension was
concentrated. Water (.about.600 mL) was added, the mixture stirred
for 45 min and then the pH was adjusted (made basic) through the
addition of .about.700 mL sat. aq. NaHCO.sub.3. The mixture was
extracted with EtOAc (3.times.300 mL). The combined organics were
washed with brine, dried (MgSO.sub.4), filtered through celite and
concentrated to give 36.86 g as an orange-red oil. MS (ESI+) m/z
248.2 (M+H.sup.+).
(5R)-1-Azabicyclo[3.2.1]octan-3-one hydrochloride
[0581] 33
[0582] A solution of (3R)-methyl
1-[(S)-1-phenylethly]pyrrolidine-3-acetat- e (25.72 g, 104.0 mmol)
in THF (265 mL) was cooled under N.sub.2 in a CO.sub.2/acetone
bath. Next, ICH.sub.2Cl (22.7 mL, 312.0 mmol) was added, and the
mixture stirred for 30 min. A solution of 2.0M lithium
diisopropylamide (heptane/THF/ethylbenzene, 156 mL, 312 mmol) was
added slowly over 30 min. The internal temperature reached a
maximum of -40.degree. C. during this addition. After 1 h, sat.
NH.sub.4Cl (100 mL) was added and the mixture was allowed to warm
to rt. The organic layer was separated, dried (MgSO.sub.4),
filtered and concentrated. The resulting red-brown foam was
chromatographed (300 g SiO.sub.2, CHCl.sub.3--MeOH--NH.sub.4OH
(89:10:1) followed by CHCl.sub.3--MeOH (3:1). The product fractions
were pooled and concentrated to afford
(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane
chloride (10.12 g) as a tan foam (MS (ESI+) m/z 230.1 (M+H.sup.+).
This foam (10.1 g, 38 mmol) was taken up in MeOH (500 mL), 10%
Pd(C) (3.0 g) added and the mixture was hydrogenated (45 psi)
overnight. The mixture was filtered and re-subjected to the
reduction conditions (9.1 g, 10% Pd/C, 50 psi). After 5 h, TLC
indicated the consumption of the (5R)-3-oxo-1-[(1S)-1-phen-
ylethyl]-1-azoniabicyclo[3.2.1]octane chloride. The mixture was
filtered, concentrated and triturated (minimal iPrOH) to give 3.73
g of (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride, in two
crops, as an off-white solid: [.alpha.].sup.25.sub.D=33 (c 0.97,
DMSO). MS (EI) m/z 125 (M.sup.+).
(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride
[0583] 34
[0584] To a flask containing (SR)-1-azabicyclo[3.2.1]octan-3-one
hydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride
(2.04 g, 29.4 mmol), and ethanol (130 mL) was added sodium acetate
trihydrate (9.23 g, 67.8 mmol). The mixture stirred for 3 h and was
filtered and concentrated. The resulting white solid was taken up
in n-propanol (100 mL) and sodium (.about.13.6 g, 618 mmol) was
added over 20-25 portions. The reaction spontaneously began to
reflux, and the reaction was heated in an oil bath (100.degree.
C.). The addition was complete in .about.20 min and the mixture had
solidified after .about.40 min. The oil bath was removed and
n-propanol (2.times.25 mL) was added dissolving the remaining
sodium metal. The mixture was carefully quenched through the
dropwise addition of H.sub.2O (100 mL). Saturated aq. NaCl (20 mL)
was added, and the layers were separated. The organic layer was
dried (MgSO.sub.4), filtered, treated with freshly prepared
MeOH/HCl, and concentrated. The resulting solid was triturated with
30 mL EtOH, filtered and dried in vaccuo to afford 3.51 g as a
white solid: [.alpha.].sup.25.sub.D=-3 (c 0.94, DMSO). MS (FAB) m/z
127 (MH.sup.+).
Preparation of endo-1-azabicyclo[3.2.1]octan-3-amine
dihydrochloride (endo-[3.2.1]-Amine)
[0585] 35
[0586] A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride
(2.80 g, 17.3 mmol), ethanol (25 mL), and hydroxylamine
hydrochloride (1.56 g, 22.4 mmol) is treated with sodium acetate
trihydrate (7.07 g, 51.2 mmol). The mixture is stirred for 3 h and
evaporated in vacuo. The residue is diluted with CH.sub.2Cl.sub.2,
treated with charcoal, filtered and evaporated. The resulting oxime
(3.1 mmol) is treated with acetic acid (30 mL) and hydrogenated at
50 psi over PtO.sub.2 (50 mg) for 12 h. The mixture is then
filtered and evaporated. The residue is taken up in a minimal
amount of water (6 mL) and the pH is adjusted to >12 using solid
NaOH. The mixture is then extracted with ethyl acetate (4.times.25
mL), dried (MgSO.sub.4), filtered, treated with ethereal HCl, and
evaporated to give the give endo-[3.2.1]-Amine.
Preparation of the 3.2.2 Amines
[0587] 36
Preparation of tert-butyl
4-(2-oxopropylidene)piperidine-1-carboxylate (Int 101)
[0588] Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) is
washed with pentane (3.times.) and suspended in dry THF (40 mL).
The solution is cooled to 0.degree. C. before diethyl
(2-oxopropyl)phosphonate (9.75 g, 50.2 mmol) is added dropwise.
After complete addition, the solution is warmed to rt and stirred
for 30 min. tert-Butyl 4-oxo-1-piperidinecarboxy- late (5.0 g, 25.1
mmol) is added in portions over 10 min, followed by stirring at rt
for 2 h. A saturated aqueous solution of ammonium chloride is
added, followed by dilution with ether. The organic layer is
extracted with water. The organic layer is dried over anhydrous
MgSO.sub.4, filtered and concentrated to a yellow oil. The crude
product is purified by flash chromatography on silica gel. Elution
with hexanes-ether (60:40) gave 4.5 g (75%)of Int 101 as a white
solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.2, 3.5, 3.4,
2.9, 2.3, 2.2, 1.5.
Preparation of tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylate
(Int 102)
[0589] A mixture of Int 101 (4.5 g, 19 mmol) and 10% palladium on
activated carbon (450 mg) in EtOH (150 mL) is placed in a Parr
bottle and hydrogenated for 5 h at 50 psi. The mixture is filtered
through Celite, and the filtrate is concentrated in vacuo to afford
4.3 g (94%) of Int 102 as a clear oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.1, 2.8, 2.4, 2.2, 2.0, 1.7, 1.5, 1.1.
Preparation of tert-butyl
4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (Int 103)
[0590] To a stirred solution lithium hexamethyldisilylamide in THF
(20. 0 mL, 1.0 M) in a -78.degree. C. bath is added
chlorotrimethylsilane (11.0 mL, 86.4 mmol) dropwise. The mixture is
stirred at -78.degree. C. for 20 min, followed by addition of Int
102 (3.21 g, 13.3 mmol) in a solution of THF (50 mL) dropwise.
After complete addition, the mixture is stirred at -78.degree. C.
for 30 min. The mixture is warmed to 0.degree. C. in an ice-water
bath and phenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) is
added. The mixture is stirred in an ice-bath for 30 min, followed
by the addition of water and ether. The aqueous layer is washed
with ether, and the combined organic layers are washed with
saturated aqueous sodium thiosulfate solution. The organic layer is
dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo
to afford a yellow oil. The crude product is purified by flash
chromatography on silica gel. Elution with hexanes-ether (60:40)
gave 2.2 g (52%) of Int 103 as a lt. yellow oil: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0, 1.7,
1.5, 1.2-1.1.2.
Preparation of 1-bromo-3-piperidin-4-ylacetone trifluoroacetate
(Int 104)
[0591] To a stirred solution of Int 103 (2.2 g, 6.9 mmol) in
CH.sub.2Cl.sub.2 (30 mL) in an ice-water bath is added
trifluoroacetic acid (10 mL, 130 mmol). The mixture is stirred at
0.degree. C. for 30 min. The volatiles are removed in vacuo to
afford 2.0 g (87%) of Int 104 as a yellow residue: MS (ESI) for
C.sub.8H.sub.15BrNO [M+H] m/e 220.
Preparation of 1-azabicyclo[3.2.2]nonan-3-one (Int 105)
[0592] To a stirred solution of DIEA (13 mL) in acetonitrile (680
mL) at reflux temperature is added a solution of Int 104 (2.0 g,
6.0 mmol) in acetonitrile (125 mL) over a 4 h period via syringe
pump. The mixture is kept at reflux temperature overnight. The
mixture is concentrated in vacuo and the remaining residue is
partitioned between a saturated aqueous potassium carbonate
solution and CHCl.sub.3-MeOH (90:10). The aqueous layer is
extracted with CHCl.sub.3-MeOH (90:10), and the combined organic
layers are dried (MgSO.sub.4), filtered and concentrated in vacuo
to a brown oil. The crude product is purified by flash
chromatography on silica gel. Elution with
CHCl.sub.3-MeOH--NH.sub.4OH (95:4.5:0.5) gives 600 mg (72%) of Int
105 as a clear solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.7, 3.3-3.2, 3.1-3.0, 2.7, 2.3, 2.0-1.8.
Preparation of 1-azabicyclo[3.2.2]nonan-3-amine
bis(4-methylbenzenesulfona- te) ([3.2.2]-Amine)
[0593] To a stirred mixture of Int 105 (330 mg, 2.4 mmol) and
sodium acetate.trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) is
added hydroxylamine.hydrochloride (200 mg, 2.8 mmol). The mixture
is stirred at rt for 10 h. The mixture is filtered and the filtrate
is concentrated in vacuo to a yellow solid. To a solution of the
solid (350 mg, 2.3 mmol) in n-propanol (30 mL) at reflux
temperature is added sodium metal (2.0 g, 87 mmol) in small
portions over 30 min. Heating at reflux is continued for 2 h. The
solution is cooled to rt and brine is added. The mixture is
extracted with n-propanol, and the combined organic layers are
concentrated in vacuo. The residue is taken up in CHCl.sub.3 and
the remaining solids are filtered. The filtrate is dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo to a clear
solid. To a stirred solution of the solid (320 mg, 2.3 mmol) in
EtOH (4 mL) is added p-toluenesulfonic acid monohydrate (875 mg,
4.6 mmol). The solution is warmed in a water bath to 45.degree. C.
for 30 min, followed by concentration of the solvent to afford 710
mg (62%) of [3.2.2]-Amine as a white solid: .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4,
2.2-2.1, 2.1-2.0, 1.9.
Resolution of Stereoisomers
[0594] The amine can be coupled to form the appropriate amides as a
racemic mixture. The racemic mixture can then be resolved by
chromatography using chiral columns or chiral HPLC, techniques
widely known in the art, to provide the requisite resolved
enantiomers 3(R) and 3(S) of said amides.
Couplings
[0595] 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. The named compounds provided
herein can be made using procedures discussed herein, making
non-critical changes and using procedures well known to those
skilled in the art. 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 invention includes the following
examples in pure stereoisomeric form or as racemic mixtures.
EXAMPLE 1
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamid-
e.hydrochloride
[0596] 37
[0597] 1-(2,3-Dihydrobenzofuran-5-yl)ethanone is made using a
procedure, making non-critical changes, as described in Dunn, J.
P.; Ackerman, N. A.; Tomolois, A. J. J. Med. Chem. 1986, 29, 2326.
Similar yield (82%) and similar purity (95%) are obtained. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.89, 7.83, 6.84, 4.70, 3.29,
2.58.
[0598] A mixture of 1-(2,3-dihydrobenzofuran-5-yl)ethanone (4.0 g,
25 mmol) and sodium hypochlorite [160 mL of a 6.0% aqueous
solution, (Clorox brand of bleach)] at 55.degree. C. is stirred for
1 h. The mixture (now homogeneous) is cooled to rt and solid sodium
bisulfite is added until a clear color persists. Hydrochloric acid
(80 mL of a 1.0 N aqueous solution) is added, followed by
extraction with EtOAc. The organic layer is washed with brine,
dried (MgSO.sub.4), filtered, and concentrated in vacuo to afford
3.93 g (97%) of 2,3-dihydrobenzofuran-5-carboxylic acid as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.0-10.3, 8.00,
6.87, 4.72, 3.31.
[0599] To a stirred solution of 2,3-dihydrobenzofuran-5-carboxylic
acid (3.96 g, 24.1 mmol) in MeOH (200 mL) is added concentrated
sulfuric acid (0.5 mL). The mixture is heated to reflux for 24 h.
The mixture is cooled to rt, followed by the addition of solid
sodium bicarbonate. The reaction mixture is concentrated in vacuo,
and the remaining residue is partitioned between EtOAc and water.
The aqueous layer is extracted with EtOAc, and the combined organic
layers are dried (MgSO.sub.4), filtered and concentrated in vacuo
to afford 4.22 g (98%) of methyl
2,3-dihydrobenzofuran-5-carboxylate as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.93-7.89, 6.82, 4.69, 3.86,
3.28.
[0600] To a stirred solution of methyl
2,3-dihydrobenzofuran-5-carboxylate (4.2 g, 24 mmol) in anhydrous
p-dioxane (150 mL) under argon atmosphere is added
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.42 g, 28 mmol). The
mixture is heated to reflux for 24 h, followed by cooling to rt.
The reaction mixture is partitioned between ether and 1/2 saturated
aqueous sodium carbonate solution. The organic layer is extracted
several times with 1/2 saturated aqueous sodium carbonate solution.
The organic layer is washed with water, dried over (MgSO.sub.4),
filtered, and concentrated in vacuo to give a mixture (92%) of
recovered starting material methyl
2,3-dihydrobenzofuran-5-carboxylate and methyl
benzofuran-5-carboxylate in a ratio of 1:3. The crude product is
purified by preparative HPLC using a Chiralcel OJ column. Elution
with heptane-iso-propyl alcohol, (80:20, flow rate=70 mL/min) gives
0.75 g (18%) of methyl 2,3-dihydrobenzofuran-5-carboxylate as a
white solid and 2.5 g (61%) of methyl benzofuran-5-carboxylate as a
white solid. .sup.1H NMR for methyl benzofuran-5-carboxylate (400
MHz, CDCl.sub.3) .delta. 8.40, 8.07, 7.73, 7.57, 6.89, 3.99.
[0601] A stirred mixture of methyl benzofuran-5-carboxylate (1.3 g,
7.38 mmol) in MeOH (51 mL) and sodium hydroxide (41 mL of a 5%
aqueous solution) is heated to 65.degree. C. for 4 h. The mixture
is cooled to rt, and MeOH is removed in vacuo. The remaining
aqueous layer is extracted with CH.sub.2Cl.sub.2. The
CH.sub.2Cl.sub.2 layer is discarded, and the aqueous layer is
acidified to pH=1 with concentrated hydrochloric acid. The aqueous
layer is extracted with CHCl.sub.3. The organic layer is washed
with water, dried (MgSO.sub.4), filtered and concentrated in vacuo
to afford 1.2 g (98%) of benzofuran-5-carboxylic acid as a white
solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.9, 8.30,
8.11, 7.92, 7.69, 7.09.
[0602] Benzofuran-5-carboxylic acid (0.16 g, 1.0 mmol) and TEA (0.8
mL, 5.7 mmol) are dissolved in 10 mL THF. Diphenylphosphinic
chloride (0.24 g, 1.0 mmol) is added dropwise. After 0.5 h,
2S-methyl-2.2.2-Amine is added, and the reaction is allowed to stir
at RT. After 3 days, 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 0.036 g (11%) of the product. HRMS (FAB)
calcd for C.sub.17H.sub.20N.sub.2O.sub.2+H 285.1603, found
285.1599.
EXAMPLE 2
N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide.fumarate
[0603] 38
[0604] To a stirred solution of 1H-indole-6-carboxylic acid (81 mg,
0.5 mmol) in anhydrous DMF (10 mL) are added DIEA (265 .mu.L, 1.52
mmol) and exo-(4S)-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is
cooled to 0.degree. C., and HATU (190 mg, 0.5 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 CHCl.sub.3. The aqueous layer is extracted with CHCl.sub.3
(2.times.). The combined organic layers are washed with brine,
dried (Na.sub.2SO.sub.4), 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 free
base as a yellow solid (84 mg, 66%).
[0605] To a stirred solution of the free base (84 mg, 0.33 mmol) in
MeOH (5 mL) is added a warm solution of fumaric acid (38 mg, 0.33
mmol) in MeOH (5 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 (5 mL). The mixture is stirred
overnight at rt. The solid is collected by filtration, washed with
acetone, and dried under high vacuum overnight gives 88 mg (72%) of
Example 2 as a white solid. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 11.38, 8.32-8.31, 7.94, 7.58-7.50, 6.54, 6.48, 3.86-3.82,
3.15-3.10, 2.97-2.89, 2.67-2.55, 1.78-1.69, 1.38-1.31.
EXAMPLE 3
N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-5-carboxamide.f-
umarate:
[0606] 39
[0607] To a stirred solution of 1-benzothiophene-5-carboxylic acid
(see: Badger et. al., J. Chem. Soc. 1957, 2624, 2628) (178 mg, 1.0
mmol) in anhydrous DMF (10 mL) are added DIEA (631 .mu.L, 3.05
mmol) and exo-(4S)-[2.2.1]-Amine (456 mg, 1.0 mmol). The mixture is
cooled to 0.degree. C., and HATU (380 mg, 1.0 mmol) is added in one
portion. The reaction mixture is allowed to warm to rt and stirred
overnight. The solvent is removed in vacuo, and the residue is
partitioned between saturated aqueous potassium carbonate solution
and CHCl.sub.3. The aqueous layer was extracted with CHCl.sub.3
(2.times.). The combined organic layers are washed with brine,
dried (Na.sub.2SO.sub.4), 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 free
base as a light yellow oil (272 mg, 100%).
[0608] To a stirred solution of the free base (272 mg, 1.0 mmol) in
MeOH (5 mL) is added a warm solution of fumaric acid (116 mg, 1.0
mmol) in MeOH (5 mL). The mixture is stirred for 5 min at
50.degree. C. The solvent is removed in vacuo, and the remaining
residue is diluted with acetone (10 mL) and water (0.2 mL). The
mixture is stirred overnight at rt. The solid is collected by
filtration, washed with acetone, and dried under high vacuum
overnight to give 300 mg (74%) of Example 3 as a white solid:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.38, 8.05-8.02,
7.85-7.83, 7.73-7.18, 7.51-7.50, 6.71, 4.29-4.26, 3.76-3.71,
3.49-3.38, 3.28-3.23, 3.09-3.08, 2.23-2.15, 1.89-1.82.
EXAMPLE 4
N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.4-met-
hylbenzenesulfonate
[0609] 40
[0610] To a stirred solution of 1-benzofuran-5-carboxylic acid (711
mg, 4.39 mmol) in anhydrous DMF (40 mL) are added DIEA (2.33 mL,
13.4 mmol) and exo-(4S)-[2.2.1]-Amine (2000 mg, 4.39 mmol). The
mixture is cooled to 0.degree. C., and HATU (1670 mg, 4.39 mmol) is
added in one portion. The reaction mixture is allowed to warm to rt
and is stirred overnight. The solvent is removed in vacuo, and the
residue is partitioned between saturated aqueous potassium
carbonate solution and CHCl.sub.3. The aqueous layer was extracted
with CHCl.sub.3 (2.times.). The combined organic layers were washed
with brine, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel. Elution with CHCl.sub.3-MeOH--NH.sub.4OH (89:9:1) gives
the free base as a white solid (1.09 g, 97.3%).
[0611] To a stirred solution of free base (1.09 g, 4.25 mmol) in
MeOH (10 mL) is added a warm solution of p-toluenesulfonic acid
monohydrate (809 mg, 4.25 mmol) in MeOH (10 mL). The mixture is
stirred for 5 min at 42.degree. C. The solvent is removed in vacuo,
and the remaining residue is diluted with acetone (25 mL). The
mixture is stirred overnight at rt. The solid is collected by
filtration, washed with acetone, and dried under high vacuum
overnight to give 1.62 g (89%) of Example 4 as a white solid:
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.19, 7.88-7.84,
7.73-7.70, 7.61-7.59, 7.25-7.23, 6.95, 4.30-4.27, 3.81-3.75,
3.55-3.42, 3.29, 3.11-3.10, 2.38, 2.26-2.17, 1.92-1.85.
EXAMPLE 5
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide
hydrochloride
[0612] 41
[0613] 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 drop-wise 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 drop-wise with
concentrated HCl (180 mL). The solid is collected via filtration,
rinsed with water and dried overnight by pulling air through the
solid to afford 13.1 g (54%) of 3-hydroxy-4-iodobenzoic acid as a
tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.13, 7.43,
7.80, 10.71, 12.98 ppm.
[0614] 3-Hydroxy-4-iodobenzoic acid (12.55 g, 47.5 mmol) is
dissolved in MeOH (200 mL), treated slowly drop-wise with thionyl
chloride (32.3 mL, 443 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 dissolves, so the mixture is filtered and the
solid is washed with a small amount of CH.sub.2Cl.sub.2 in 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 (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.7IO.sub.3+H: 278.9520, found 278.9521
(M+H).sup.+.
[0615] 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. Triethylamine (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 (MgSO.sub.4) and concentrated to a brown
oily-solid (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: 249.0947, found
249.0947 (M+H).sup.+.
[0616] Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (3.0 g,
12.1 mmol) is dissolved in 1:1 EtOH/Et.sub.3N (30 mL), is treated
with CuI (114 mg, 0.6 mmol), and the reaction is warmed to
75.degree. C. for 3 h. The mixture is treated with DARCO and MeOH
(15 mL) and heated to reflux for 1 h. The reaction is filtered
through a fine fritted-glass funnel, the filtrate is treated with
3N NaOH (24.2 ml, 72.5 mmol), and the mixture is stirred overnight
at RT. The mixture is concentrated to dryness, the residue is
dissolved in H.sub.2O (20 mL), and the pH of the mixture is
adjusted to 2 with 12N HCl. The resulting yellow precipitate is
collected, washed with water, and is dried to give 1.83 g (93%) of
benzofuran-6-carboxylic acid as a tan solid. HRMS (FAB) calcd for
C.sub.9H.sub.6O.sub.3+H: 163.0395, found 163.0389 (M+H).sup.+.
[0617] Method A:
[0618] 1-Benzofuran-6-carboxylic acid (162 mg, 1.0 mmol) is
combined with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1
mmol), DEEA (522 .mu.L, 3.0 mmol) and DMF (5 .mu.L), cooled to
0.degree. C., treated with HATU (380 mg, 1.0 mmol) and stirred for
18 h as the cooling bath expired. The mixture is concentrated under
high vacuum and partitioned between a 1:1 solution of saturated
NaCl/conc. NH.sub.4OH (10 mL) and CHCl.sub.3 (3.times.10 mL). The
organics are dried (Na.sub.2SO.sub.4) and concentrated to an oil
(530 mg). The crude material is chromatographed over 11 g
slurry-packed silica gel, eluting with 2% conc. NH.sub.4OH/10%
MeOH/CHCl.sub.3. The appropriate fractions are combined and
concentrated to a dark yellow solid (274 mg). The solid is placed
under high vacuum, dissolved in MeOH (5 mL), treated with 3N HCl
MeOH (1 mL), stirred for 16 h, then concentrated to dryness. The
residue is dissolved in MeOH (1 mL) and IPA (10 mL) and treated
with Et.sub.2O (.about.20 mL) until turbid. The mixture is stirred
for 16 h, filtered under nitrogen and dried in a vacuum oven at
50.degree. C. to afford 206 mg (67%) of Example 5 as an off-white
solid. HRMS (FAB) calcd for C.sub.16H.sub.18N.sub.2O.sub.2+H:
271.1446, found 271.1447 (M+H).sup.+.
EXAMPLE 6
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide
hydrochloride
[0619] 42
[0620] 4-Hydroxybenzoic acid (34.5 g, 250 mmol) is suspended in
MeOH (500 mL), treated with NaI (34.5 g, 250 mmol) and NaOH (20 g,
500 mmol) and cooled to 0.degree. C. Sodium hypochlorite (Clorox
bleach) (423 mL, 250 mmol) is added slowly drop-wise at 0-5.degree.
C. and the mixture is stirred for 1 h. The mixture is treated with
saturated Na.sub.2S.sub.2O.sub.3 (135 mL) and water (135 mL) and
stirred overnight as the cooling bath expired. The mixture is
acidified to pH 3.5 with concentrated HCl and the resulting
precipitate filtered off. The solid contained a mixture of the
desired mono-iodo product and the iodo-chloro and the bis-iodo
byproducts; it is discarded. The filtrate is concentrated to
dryness, partitioned between H.sub.2O (300 mL) and EtOAc
(1.times.500 mL, then 3.times.300 mL), dried (Na.sub.2SO.sub.4) and
concentrated to afford 59.6 g (90%) of 4-hydroxy-3-iodobenzoic acid
as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
6.95, 7.80, 8.22 ppm.
[0621] 4-Hydroxy-3-iodobenzoic acid (59.6 g, 226 mmol) is combined
with 3N HCl/MeOH (276 mL, 678 mmol) and heated to 65.degree. C. for
24 h, then concentrated to dryness. The residue is diluted with
water, neutralized to pH 7 with 3N NaOH and the resulting solid
collected via filtration. The crude material is adsorbed onto
silica gel and chromatographed over 1 kg of silica gel with 50%
EtOAc/hexane. Fractions containing product are combined and
concentrated to a solid (47.2 g). The material is recrystallized
from EtOAc to afford 22.8 g (36%) of methyl
4-hydroxy-3-iodobenzoate as a white solid. HRMS (FAB) calcd for
C.sub.8H.sub.7IO.sub.3+H: 278.9520, found 278.9534 (M+H).sup.+.
[0622] Methyl 4-hydroxy-3-iodobenzoate (5.56 g, 20 mmol) is
combined with trimethylsilylacetylene (3.96 mL, 28 mmol),
bis(triphenylphosphine)pallad- ium dichloride (414 mg, 0.6 mmol)
and cuprous iodide (57 mg, 0.3 mmol) in THF (20 mL)/CHCl.sub.3 (40
mL) in a dry flask, under nitrogen. TEA (8.7 mL, 62.3 mmol) is
added and the mixture 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 (MgSO.sub.4) and concentrated to a brown solid. The
crude material is adsorbed onto silica gel and chromatographed over
200 g silica gel, eluting with 15% EtOAc/hexane (2 L) followed by
20% EtOAc/hexane (1 L). Fractions are combined and concentrated to
afford 2.50 g (50%) of methyl
4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate as a yellow solid.
HRMS (FAB) calcd for C.sub.13HI.sub.6O.sub.3SI+H: 249.0947, found
249.0955 (M+H).sup.+.
[0623] Methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate (11 g,
44.5 mmol) is combined with CuI (423 mg, 2.2 mmol) and DIA (7.1 ml,
50 mmol) in MeOH (110 mL) in a flask under nitrogen. The reaction
is warmed to 60.degree. C. for 6 h, the volatiles are removed in
vacuo, and the brown-green residue is chromatographed over 500 g
silica gel (230-400 mesh) eluting with 20% EtOAc/hexane. Two pools
are isolated to provide 3.43 g (31%) of the early eluting methyl
2-trimethylsilylbenzofuran-5-car- boxylate and 2.63 g (33%) of the
later eluting methyl benzofuran-5-carboxylate. The pools are
combined in MeOH (130 mL). The solution is treated with 2N NaOH
(46.8 ml, 93.6 mmol), is warmed to 50.degree. C., and is stirred
for 2 h. The mixture is cooled, the volatiles are removed in vacuo,
and the residue is dissolved in water (50 mL). The pH of the
mixture is adjusted to 2 with 12N HCl, is diluted with water (40
mL), and the mixture is cooled to 0.degree. C. The off-white solid
is collected, washed with water, and is dried to give 6.0 g. The
solid is dried in vacuo over P.sub.2O.sub.5 for 18 h to give 4.6 g
(99%) of benzofuran-5-carboxylic acid as an off-white solid. MS for
C.sub.9H.sub.6O.sub.3, (ED) m/z: 162 (M).sup.+.
[0624] Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is
dissolved in DMF (15 ml) in a dry flask under nitrogen with
propargyl trimethylsilane (1.19 ml, 7.98 mmol),
bis(triphenylphosphine)palladium dichloride (71 mg, 0.10 mmol),
copper iodide (55 mg, 0.29 mmol), and piperidine (1.14 ml, 11.5
mmol). The reaction is heated at 45.degree. C. for 7 h and then
stirred at RT overnight. The reaction mixture is diluted with EtOAc
(75 ml) and washed with a 50% saturated solution of 1: 1
NaCl/NaHCO.sub.3 (4.times.25 ml). The organic layer is dried
(Na.sub.2SO.sub.4) and concentrated to an amber oil. The crude
material is chromatographed over 100 g slurry-packed silica gel,
eluting with 20% EtOAc/hexane. The appropriate fractions are
collected and concentrated to afford 1.5 g of a mixture methyl
2-methyl-benzofuran-5-carboxylate and the corresponding
2-TMS-methyl derivative, neither of which is isolated independently
from one another. The mixture of esters is dissolved in MeOH (15
ml) and water (1 ml) and treated with 2N NaOH (3.15 ml, 6.3 mmol).
After 2 days, the volatiles are removed in vacuo and the residue is
dissolved in H.sub.2O (5 ml). TLC indicated the presence of 2
spots, so the solution is washed with Et.sub.2O (3.times.10 ml) to
remove the undesired reaction component. The pH is then adjusted to
3 with concentrated HCl and the resulting slurry is filtered. The
isolated cake is dried overnight to yield 789 mg (85%) of
2-methyl-1-benzofuran-6-carboxylic acid as a pale yellow solid. MS
for C.sub.10H8O.sub.3, (EI) m/z: 176 (M).sup.+.
[0625] 2-Methyl-1-benzofuran-6-carboxylic acid (176 mg, 1.0 mmol)
is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg,
1.1 mmol) and the salt is made as described in Method A with
non-critical changes to afford 282 mg (88%) of Example 6 as a white
solid. HRMS (FAB) calcd for C.sub.17H.sub.20N.sub.2O.sub.2+H:
285.1603, found 285.1586 (M+H).sup.+.
EXAMPLE 7
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide
hydrochloride
[0626] 43
[0627] Methyl 4-hydroxy-3-iodobenzoate (3.0 g, 10.8 mmol) is
dissolved in DMF (25 ml) in a dry flask under nitrogen with
propargyl trimethylsilane (1.79 ml, 11.9 mmol),
bis(triphenylphosphine)palladium dichloride (106 mg, 0.15 mmol),
copper iodide (82 mg, 0.4 mmol), and piperidine (1.71 ml, 17.2
mmol). The reaction is heated at 45.degree. C. for 7 h and then at
RT overnight. The reaction mixture is diluted with EtOAc (125 ml)
and washed with 1:1 saturated NaCl/NaHCO.sub.3 (4.times.50 ml). The
organic is dried (Na.sub.2SO.sub.4) and concentrated to an oil. The
crude material is chromatographed over 100 g slurry-packed silica
gel, eluting with 15% EtOAc/hexane. The fractions containing the
desired product are collected and concentrated to afford 2.4 g
(85%) of intermediate
methyl-2-trimethylsilylmethyl-benzofuran-5-carboxylate as an orange
oil. The oil is dissolved in MeOH (25 ml) and H.sub.2O (3 ml) and
treated with 2N NaOH (5.1 ml, 10.2 mmol). The reaction is monitored
by TLC and required slight heating at 45.degree. C. for 6 h. An
additional amount of 2N NaOH (5.0 ml, 10.0 mmol) is required to
complete the hydrolysis. The volatiles are removed in vacuo, and
the residue is dissolved in Et.sub.2O (15 ml). The pH is adjusted
to 3 with 12N HCl and the resulting slurry is filtered. The
isolated cake is dried overnight to yield 1.5 g (94%) of
2-methyl-1-benzofuran-5-carboxylic acid as a gray solid. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 2.47, 6.70, 7.57, 7.85, 8.16,
12.81 ppm.
[0628] 2-Methyl-1-benzofuran-5-carboxylic acid (176 mg, 1.0 mmol)
is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg,
1.1 mmol) and the salt is made according to Method A with
non-critical changes to afford 273 mg (85%) of Example 7 as a white
solid. HRMS (FAB) calcd for C.sub.17H.sub.20N.sub.2O.sub.2+H:
285.1603, found 285.1606 (M+H).sup.+.
EXAMPLE 8
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide
[0629] 44
[0630] A dried flask under nitrogen is charged with methyl
3-hydroxy-4-iodobenzoate (10.0 g, 35.9 mmol), propioaldehyde
diethyl acetal (5.72 ml, 40.0 mmol), bistriphenylphosphine
palladium diacetate (538 mg, 0.72 mmol), copper iodide (273 mg, 1.4
mmol) and piperidine (3.94 ml, 40.0 mmol) in DMF (50 ml). The
mixture is stirred at 45.degree. C. for 6 h, then at RT overnight.
The reaction is diluted with EtOAc (250 ml) and washed with 50%
saturated 1:1 NaCl/NaHCO.sub.3 solution (4.times.100 ml). The
organic layer is dried (Na.sub.2SO.sub.4), filtered and
concentrated to a brown oil. The crude material is chromatographed
over 500 g slurry-packed silica, eluting with 15% EtOAc/hexane. The
appropriate fractions are collected and concentrated, affording
3.22 g (32%) of methyl
2-(diethoxymethyl)-l-benzofuran-6-carboxylate as an orange oil.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.29, 3.72, 3.96, 5.70,
6.88, 7.61, 7.95, 8.20 ppm.
[0631] Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (2.71
g, 9.7 mmol) is treated drop-wise with formic acid (20 ml, 530
mmol) and water (5.5 ml). The reaction is stirred overnight at RT,
diluted with water (50 ml), and the brown slurry is filtered. The
cake is dried overnight to afford 1.86 g (94%) of methyl
2-formyl-1-benzofuran-6-carboxylate as an amber solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 3.91, 8.03, 8.28, 9.92 ppm.
[0632] Hydroxylamine hydrochloride (153 mg, 2.2 mmol) is free based
for 5 min in 2N NaOH (1.1 ml, 2.2 mmol) and added drop-wise to a
solution of methyl 2-formyl-1-benzofuran-6-carboxylate (408 mg, 2.0
mmol) in EtOH (6 ml). The reaction is stirred overnight and the
volatiles are removed in vacuo. The residue is suspended in water
(5 ml) and the slurry is filtered. The cake is dried overnight to
afford 399 mg (91%) of E/Z-methyl
2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate as a light
brown solid. HRMS (FAB) calcd for C.sub.11H.sub.9NO.sub.4+H:
220.0610, found 220.0602 (M+H).sup.+.
[0633] E/Z-Methyl
2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate (438 mg, 2.0
mmol) is suspended in CH.sub.2Cl.sub.2 (8 ml) in a dry flask under
nitrogen. Pyridine (0.65 ml, 8.0 mmol) is added via syringe, and
the mixture is cooled to 0.degree. C. Trifluoroacetic anhydride
(0.56 ml, 4.0 mmol) is added drop-wise, and the reaction is stirred
overnight, allowing the ice bath to expire. The reaction is
carefully quenched with saturated NaHCO.sub.3 (10 ml). The layers
are separated and the organic layer is dried (K.sub.2CO.sub.3),
filtered, and concentrated to a pink solid. The crude material is
chromatographed over 25 g slurry-packed silica gel, eluting with
25% EtOAc/hexane. The appropriate fractions are collected and
concentrated to afford 315 mg (78%) of methyl
2-cyano-1-benzofuran-6-carboxylate as a white solid.
[0634] Methyl 2-cyano-1-benzofuran-6-carboxylate (250 mg, 1.24
mmol) is suspended in pH=7.0 buffer (20 ml). Pig liver esterase (41
units/mg) (150 mg, 6.21 milli-equivalents) is dissolved in pH 7.0
buffer and added drop-wise to the suspension. The reaction is
stirred vigorously overnight and is monitored by TLC. The mixture
is filtered through celite, and the pH of the liquor is adjusted to
3 with concentrated HCl. The white, milky solution is filtered
through a fine frit, and the resulting cake is dried overnight,
yielding 246 mg (>100%, water present) of
2-cyano-1-benzofuran-6-carboxylic acid as a gray solid. MS (EI)
m/z: 187 (M).sup.+.
[0635] 2-Cyano-1-benzofuran-6-carboxylic acid (226 mg, 1.2 mmol) is
coupled with (R)-3-aminoquinuclidine dihydrochloride (265 mg, 1.33
mmol) and the salt is made according to Method A with non-critical
changes to afford 268 mg (75%) of Example 8 as a white solid. HRMS
(FAB) calcd for C.sub.17H.sub.17N.sub.3O.sub.2+H: 296.1399, found
296.1398 (M+H).sup.+.
EXAMPLE 9
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-5-carboxamide
fumarate
[0636] 45
[0637] Methyl 4-hydroxy-3-iodo-benzoate (9.9 g, 35 mmol) is
combined with propioaldehyde diethylacetal (5.6 ml, 39 mmol),
bis(triphenylphosphine)pa- lladium(II) chloride (523 mg, 0.7 mmol),
cuprous iodide (266 mg, 1.4 mmol), and piperidine (3.9 ml, 39 mmol)
in DMF (50 ml) in a dry flask under nitrogen. The reaction is
warmed to 60.degree. C. for 6 h and is stirred overnight at RT. The
mixture is diluted with EtOAc (250 ml) and is washed with 2:1:1:0.1
water/brine/saturated NaHCO.sub.3/conc. NH.sub.4OH (4.times.100
ml). The organic layer is dried (MgSO.sub.4) and is concentrated in
vacuo to a dark oil. The crude material is chromatographed over 300
g silica gel (230-400 mesh), eluting with 15% EtOAc/hexane. The
appropriate fractions are combined and concentrated to afford 5.2 g
(48%) methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylate as an
amber oil. HRMS (EI) calcd for C.sub.15H.sub.18O.sub.5: 278.1154,
found 278.1156 (M).sup.+.
[0638] Methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylate (2.6 g,
8.5 mmol) is combined with formic acid (15 ml) and water (3.8 ml).
The reaction is stirred 6 h at RT, the volatiles are removed in
vacuo, and the residue is neutralized with 50 ml saturated
NaHCO.sub.3. The mixture is extracted with CH.sub.2Cl.sub.2
(4.times.20 ml), the organic layer is dried (K.sub.2CO.sub.3), and
is concentrated in vacuo to provide 1.72 g (99%) of methyl
2-formyl-1-benzofuran-5-carboxylate as amber flakes. HRMS (EI)
calcd for C.sub.11H.sub.8O.sub.4: 204.0423, found 204.0418
(M).sup.+.
[0639] Methyl 2-formyl-1-benzofuran-5-carboxylate (1.64 g, 8.0
mmol) is dissolved in ethanol (30 ml). The solution is treated with
hydroxylamine hydrochloride (614 mg, 8.8 mmol) in 2N NaOH (4.2 ml),
and the reaction is stirred overnight at RT. The reaction mixture
is concentrated to dryness, the residue is triturated with water,
collected, and dried to give 1.7 g (97%) of methyl
2-[(E,Z)-(hydroxyimino)methyl]-1-benzofuran-5-carboxylate as a pale
yellow solid. HRMS (EI) calcd for C.sub.11H.sub.9NO.sub.4:
219.0531, found 219.0536 (M).sup.+.
[0640] Methyl
2-[(E,Z)-(hydroxyimino)methyl]-1-benzofuran-5-carboxylate (1.65 g,
7.53 mmol) is dissolved in CH.sub.2Cl.sub.2 (40 ml) in a dry flask
under nitrogen. The solution is treated with pyridine (2.5 ml, 30.1
mmol) followed by trifluoroacetic anhydride (2.10 ml, 15.1 mmol),
and the reaction is stirred 4 h at RT. The reaction mixture is
washed with 5% aqueous HCl (100 ml) followed by saturated
NaHCO.sub.3 (100 ml), the organic layer is dried (K.sub.2CO.sub.3),
and is concentrated in vacuo to a pale yellow solid. The crude
material is chromatographed over 50 g silica gel (230-400 mesh)
eluting with 10% EtOAc/hexane. The appropriate fractions are
combined and concentrated in vacuo to give 700 mg (44%) of methyl
2-cyano-1-benzofuran-5-carboxylate as a white solid. .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 3.98, 7.55, 7.60, 8.23, 8.44
ppm.
[0641] Methyl 2-cyano-1-benzofuran-5-carboxylate (126 mg, 0.62 mmol
) is suspended in pH 7.0 buffer (7 ml). Pig Liver Esterase (41
units/mg) (76 mg, 3.13 milli-equivalents) is dissolved in pH 7.0
buffer (3 ml) and added drop-wise to the suspension. The reaction
is stirred vigorously overnight and monitored by TLC. The mixture
is filtered through celite, and the pH of the liquor is adjusted to
3 with concentrated HCl. The white, milky solution is filtered
through a fine frit, and the resulting cake is dried overnight,
yielding 122 mg (>100%, water present) of
2-cyano-1-benzofuran-5-carboxylic acid as a crunchy, tan solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.85, 8.16, 8.21, 8.45
ppm.
[0642] 2-Cyano-1-benzofuran-5-carboxylic acid (129 mg, 0.7 mmol) is
coupled with (R)-3-aminoquinuclidine dihydrochloride (151 mg, 0.75
mmol) according to Method A except that the free base is dissolved
in methanol (1 ml) and EtOAc (8 ml). Fumaric acid (41 mg, 0.37
mmol) is added portionwise, and the mixture stirred overnight. The
volatiles are removed in vacuo, to afford 123 mg (43%) of Example 9
as a white solid. MS (EI) m/z: 295 (M).sup.+.
EXAMPLE 10
N-6-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxamide
[0643] 46
[0644] Methyl 2-formyl-1-benzofuran-6-carboxylate (1.23 g, 6.0
mmol) is dissolve in DMSO (12 ml). KH.sub.2PO.sub.4 (229 mg, 1.68
mmol) in H.sub.2O (2 ml) and NaClO.sub.2 (80%, 949 mg, 8.4 mmol) in
H.sub.2O (12 ml) are added drop-wise to the solution, and the
reaction is stirred over the weekend at RT. The pH is adjusted to
10 with 2N NaOH and the mixture is extracted with Et.sub.2O
(3.times.50 ml). The pH is adjusted again to 3 with concentrated
HCl and the slurry is filtered. The cake is dried overnight,
yielding 1.07 g (81%) of 6-(methoxycarbonyl)-1-benzofuran-2-ca-
rboxylic acid as an ivory solid. HRMS (FAB) calcd for
C.sub.11H.sub.8O.sub.5+H: 221.0450, found 221.0436 (M+H).sup.+.
[0645] 6-(Methoxycarbonyl)-1-benzofuran-2-carboxylic acid (220 mg,
1.0 mmol) is combined with HATU (570 mg, 1.5 mmol) in DMF (4 mL).
The mixture is treated portionwise with DIEA (350 .mu.L, 2.0 mmol)
and NH.sub.4Cl (183 mg, 3.4 mmol) and stirred for 3 h. The mixture
is diluted with saturated NaCl (50 mL) and extracted with EtOAc
(3.times.20 mL). The combined organics are washed with 2N HCl
(2.times.10 mL), followed by water (2.times.10 mL), saturated
NaHCO.sub.3 (2.times.10 mL) and additional H.sub.2O (2.times.10 mL)
then dried (Na.sub.2SO.sub.4) and concentrated to afford 177 mg
(81%) of methyl 2-(aminocarbonyl)-1-benzofu- ran-6-carboxylate as
an orange-brown solid. HRMS (FAB) calcd for
C.sub.11H.sub.9NO.sub.4+H: 220.0610, found 220.0603 M+H).sup.+.
[0646] Methyl 2-(aminocarbonyl)-1-benzofuran-6-carboxylate(164 mg,
0.75 mmol) is dissolved in MeOH (5 mL) and water (1 mL), treated
drop-wise with 2N NaOH (450 .mu.L, 0.9 mmol) and monitored by TLC.
The volatiles are removed in vacuo, and the resulting tan solid is
dissolved in water (5 mL) and acidified to pH 3 with concentrated
HCl. The resulting solid is collected via filtration and dried in a
vacuum oven with heat 50.degree. C. to afford 142 mg (93%) of
2-(aminocarbonyl)-1-benzofuran-6-- carboxylic acid as an orange
solid. HRMS (EI) calcd for C.sub.10H.sub.7NO.sub.4: 205.0375, found
205.0378 (M).sup.+.
[0647] 2-(Aminocarbonyl)-1-benzofuran-6-carboxylic acid (131 mg,
0.64 mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride
(140 mg, 0.7 mmol) according to Method A to afford 174 mg (87%) of
Example 10 as a pale yellow solid. HRMS (FAB) calcd for
C.sub.17H.sub.19N.sub.3O.sub.3+H: 314.1505, found 314.1502
(M+H).sup.+.
EXAMPLE 11
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide.fumara-
te
[0648] 47
[0649] 1-Benzothiophene-6-carboxylic acid [see: Badger et al. J.
Chem. Soc. 1957, 2624, 2628] is coupled with
(R)-3-aminoquinuclidine dihydrochloride according to Method C
making non-critical changes to give the free base as a white solid
(260 mg, 95%) and Example 11 as a white solid (260 mg, 71%):
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.48, 7.95, 7.87, 7.80,
7.48, 6.71, 4.52-4.45, 3.89-3.80, 3.50-3.25, 2.41-2.36, 2.33-2.23,
2.15-2.08, 2.00-1.88.
EXAMPLE 12
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide.fumara-
te
[0650] 48
[0651] 1-Benzothiophene-5-carboxylic acid is coupled with
(R)-3-aminoquinuclidine dihydrochloride according to Method C
making non-critical changes to give the free base as a white solid
(256 mg, 90%) and Example 12 as a white solid (260 mg, 71%):
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.40, 8.03, 7.84, 7.71,
7.50, 6.71, 4.50-4.45, 3.90-3.82, 3.52-3.28, 2.40-2.36, 2.33-2.21,
2.16-2.08, 2.01-1.90.
EXAMPLE 13
N'5'-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxamide
[0652] 49
[0653] Methyl 2-cyano-1-benzofuran-5-carboxylate (426 mg, 2.0 mmol)
is dissolved in MeOH (10 ml). The solution is cooled to 0.degree.
C., is treated with LiOH monohydrate (168 mg, 4.0 mmol) in H.sub.2O
(4 ml), and the reaction is stirred 6 h at RT. The volatiles are
removed in vacuo and the residue is dissolved in H.sub.2O (10 ml).
The pH of the mixture is adjusted to 1.9 with 12N HCl, the white
solid is collected, washed with water, and is dried to give 401 mg
(97%) of 2-(aminocarbonyl)-1-benzofura- n-5-carboxylic acid as an
off-white solid. MS (EI) calcd for C.sub.10H.sub.7NO.sub.4:
205.0375, found 205.0369 (M).sup.+.
[0654] 2-(Aminocarbonyl)-1-benzofuran-5-carboxylic acid (350 mg,
1.7 mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride
(374 mg, 1.9 mmol) according to Method A to afford 120 mg (23%) of
Example 13 as white solid. HRMS (ESI) calcd for
C.sub.17H.sub.19N.sub.3O.sub.3+H: 314.1505, found 314.1513
(M+H).sup.+.
EXAMPLE 14
2-Acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide
hydrochloride
[0655] 50
[0656] Methyl 2-formyl-1-benzofuran-6-carboxylate (750 mg, 3.67
mmol) is dissolved in anhydrous THF (30 ml) in a dry flask under
nitrogen and cooled to 0.degree. C. Methyl magnesium bromide (2.6
ml, 3.67 mmol) is added via syringe, and the reaction is stirred
overnight, allowing the ice bath to expire. The reaction is
quenched with 5% HCl (70 ml) and extracted with CH.sub.2Cl.sub.2
(3.times.25 ml). The combined organics are dried (MgSO.sub.4),
filtered, and concentrated to a yellow oil. The crude material is
chromatographed over 100 g slurry-packed silica gel, eluting with
35% EtOAc/hexane. The appropriate fractions are collected and
concentrated to afford 412 mg (51%) of methyl
2-(1-hydroxyethyl)-1-be- nzofuran-6-carboxylate as a yellow oil
that solidified upon standing. MS for C.sub.12H].sub.2O.sub.4, (EI)
m/z: 220 (M).sup.+.
[0657] Oxalyl chloride (0.1 ml, 1.15 mmol) is dissolved in
CH.sub.2Cl.sub.2 (2 ml) in a dry flask under nitrogen and cooled to
-78.degree. C. DMSO (0.16 ml, 2.3 mmol) is added drop-wise, and the
mixture stirred for 30 min, while maintaining the temperature.
Methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate (220 mg, 1.0
mmol) is dissolved in CH.sub.2Cl.sub.2 (2 ml) and added drop-wise
to the mixture, and the solution stirred for 1 h at -78.degree. C.
TEA (0.69 ml, 5.0 mmol), is added drop-wise and the reaction is
stirred for an additional 30 min. The reaction is then warmed to
0.degree. C. and stirred for another 30 min. The reaction is washed
with saturated NaHCO.sub.3 (40 ml), and the organics are dried
(K.sub.2CO.sub.3), filtered, and concentrated to a yellow solid.
The crude material is chromatographed over 25 g slurry-packed
silica gel, eluting with 20% EtOAc/hexane. The appropriate
fractions are collected and concentrated to afford 174 mg (80%) of
methyl 2-acetyl-1-benzofuran-6-carboxylate as a pale yellow solid.
HRMS (FAB) calcd for C.sub.12H.sub.10O.sub.4+H: 219.0657, found
219.0667 (M+H).sup.+.
[0658] Methyl 2-acetyl-1-benzofuran-6-carboxylate (155 mg, 0.71
mmol) is dissolved in MeOH (3 ml) and H.sub.2O (0.5 ml). 2N NaOH
(0.39 ml, 0.78 mmol) is added drop-wise, and the reaction is
stirred overnight. The volatiles are removed in vacuo, and the
residue is dissolved in H.sub.2O (3 ml). Concentrated HCl is used
to adjust the pH to 3, and the resulting precipitate is isolated
via filtration and dried overnight to afford 135 g (93%) of
2-acetyl-1-benzofuran-6-carboxylic acid as a yellow solid. MS for
C.sub.11H.sub.8O.sub.4, (ESI-) m/z: 202.7 (M-H).sup.-.
[0659] 2-Acetyl-1-benzofuran-6-carboxylic acid (130 mg, 0.64 mmol)
is coupled with (R)-3-aminoquinuclidine dihydrochloride (140 mg,
0.70 mmol) and salt made according to Method A with non-critical
variations to afford 176 mg (79%) of Example 14 as a yellow solid.
HRMS (FAB) calcd for C.sub.18H.sub.20N.sub.2O.sub.3+H: 313.1552,
found 313.1552 (M+H).sup.+.
EXAMPLE 15
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide
[0660] 51
[0661] Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (417
mg, 1.5 mmol) is dissolved in MeOH (8 ml) and H.sub.2O (2 ml). 2N
NaOH (0.9 ml, 1.8 mmol) is added drop-wise, and the reaction is
stirred for 4 days. The volatiles are removed in vacuo and the
residue is dissolved in H.sub.2O (2 ml). Concentrated HCl is used
to adjust the pH to 3, and the resulting precipitate is isolated
via filtration and dried overnight to afford 410 mg (>100%,
water present) of 2-(diethoxymethyl)-1-benzofuran-6-carboxy- lic
acid as a brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
1.29, 3.72, 6.9, 7.66, 8.04, 8.29 ppm.
[0662] 2-(Diethoxymethyl)-1-benzofuran-6-carboxylic acid (264 mg,
1.0 mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride
(219 mg, 1.1 mmol) and salt made according to Method A with
non-critical changes to afford 286 mg (70%) of
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(diethox-
ymethyl)-1-benzofuran-6-carboxamide hydrochloride as a white solid.
HRMS (FAB) calcd for C.sub.21H.sub.28N.sub.2O.sub.4+H: 373.2127,
found 373.2121 (M+H).sup.+.
[0663]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-(diethoxymethyl)-1-benzofura-
n-6-carboxamide hydrochloride (100 mg, 0.24 mmol) is dissolved in
formic acid (1 ml, 26 mmol), treated drop-wise with H.sub.2O (0.25
ml) and stirred overnight. The volatiles are removed in vacuo, the
residue treated carefully with saturated NaHCO.sub.3 (5 ml) and
stirred for 15 min. The precipitate is isolated via filtration and
the cake dried overnight to yield 58 mg (80%) of Example 15 as a
light tan solid. HRMS (FAB) calcd for
C.sub.17H.sub.18N.sub.2O.sub.3+H: 299.1396, found 299.1402
(M+H).sup.+.
EXAMPLE 16
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide
hydrochloride
[0664] 52
[0665] Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is
dissolved in DMF (25 ml) in a dry flask under nitrogen. Allyl
bromide (0.65 ml, 7.55 mmol) is added drop-wise, followed by the
careful addition of 60% NaH (303 mg, 7.55 mmol). The reaction is
stirred overnight at RT and then is diluted with H.sub.2O (30 ml).
The mixture is extracted with EtOAc (3.times.30 ml), and the
combined organics are washed with 50% saturated NaCl (4.times.25
ml), dried (MgSO.sub.4), filtered, and concentrated under high
vacuum to an oil that solidified upon standing. The volatiles are
removed in vacuo to obtain 2.28 g (100%) of methyl
3-(allyloxy)-4-iodobenzoate as a tan solid. HRMS (FAB) calcd for
C.sub.11H.sub.11IO.sub.3+H: 318.9833, found 318.9831
(M+H).sup.+.
[0666] Methyl 3-(allyloxy)-4-iodobenzoate (2.0 g, 6.28 mmol) is
dissolved in DMF (15 ml), treated with Pd(OAc).sub.2 (71 mg, 0.31
mmol), Na.sub.2CO.sub.3 (1.67 g, 15.7 mmol), sodium formate (427
mg, 6.28 mmol), and n-Bu.sub.4NCl.H.sub.2O (1.92 g, 6.92 mmol) and
stirred at 80.degree. C. for 2 days. The mixture is then filtered,
the liquor is diluted with EtOAc (75 ml) and washed with 50%
saturated NaCl (4.times.25 ml) followed by 5% HCl (25 ml). The
organic layer is dried (Na.sub.2SO.sub.4), filtered, and
concentrated to a brown oil. The crude material is chromatographed
over 50 g slurry-packed silica gel, eluting with 20% EtOAc/hexane.
The appropriate fractions are combined and concentrated to afford
797 mg (67%) of methyl 3-methyl-1-benzofuran-6-carboxylate as a
pale oil. HRMS (FAB) calcd for C.sub.11H.sub.10O.sub.3+H: 191.0708,
found 191.0714 (M+H).sup.+.
[0667] Methyl 3-methyl-1-benzofuran-6-carboxylate (720 mg, 3.78
mmol) is dissolved in MeOH (10 ml), treated with 2N NaOH (2.27 ml,
4.5 mmol) and stirred overnight. The volatiles are removed in
vacuo, the residue is dissolved in H.sub.2O (5 ml) and the pH is
adjusted to 3 with concentrated HCl. The mixture is stirred
overnight and the resulting solid is filtered to afford 545 mg
(82%) of 3-methyl-1-benzofuran-6-carbo- xylic acid as a white
solid. HRMS (FAB) calcd for C.sub.10H.sub.8O.sub.3+H- : 177.0552,
found 177.0551 (M+H).sup.+.
[0668] 3-Methyl-1-benzofuran-6-carboxylic acid (176 mg, 1.0 mmol)
is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg,
1.1 mmol) and salt made according to Method A with non-critical
variations to afford 244 mg (76%) of Example 16 as a white solid.
HRMS (FAB) calcd for C.sub.17H.sub.20N.sub.2O.sub.2+H: 285.1603,
found 285.1616 (M+H).sup.+.
EXAMPLE 17
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide
hydrochloride
[0669] 53
[0670] Methyl 4-hydroxy-3-iodobenzoate (1.85 g, 6.65 mmol) is
dissolved in anhydrous DMF (15 mL) in a dry flask under nitrogen,
treated with NaH (60% dispersion in oil, 265 mg, 6.65 mmol) and
stirred for 1 h at RT. Allyl bromide (633 .mu.L, 7.32 mmol) is
added and the mixture is stirred for 16 h. The mixture is
concentrated and the residue is partitioned between EtOAc (25 mL)
and H.sub.2O (25 mL). The organic layer is washed with a 50%
saturated mixture of 1:1 NaC/NaHCO.sub.3 (2.times.10 mL), dried
(MgSO.sub.4) and concentrated to a yellow oil which solidified to a
white solid upon standing (2.12 g). The crude material is
chromatographed over 100 g slurry-packed silica gel, eluting with
10% EtOAc/hexane. The appropriate fractions are combined and
concentrated to afford 1.27 g (60%) of methyl
4-(allyloxy)-3-iodobenzoate as a colorless oil which solidified on
standing. MS for C.sub.11H.sub.11IO.sub.3 (ED) m/z: 318
(M).sup.+.
[0671] Methyl 4-(allyloxy)-3-iodobenzoate (587 mg, 1.84 mmol) is
combined with Pd(OAc).sub.2 (5%, 20 mg, 0.1 mmol), Na.sub.2CO.sub.3
(487 mg, 4.6 mmol), sodium formate (125 mg, 1.8 mmol) and
n-Bu.sub.4NCl.H.sub.2O (561 mg, 2.0 mmol) in DMF (5 mL) and heated
to 80.degree. C. for 2 days. The mixture is concentrated under high
vacuum and partitioned between 50% saturated NaCl (10 mL) and
CH.sub.2Cl.sub.2 (4.times.10 mL). The combined organics are washed
with 5% HCl (10 mL), dried (Na.sub.2SO.sub.4) and concentrated to a
brown oil. The crude material is chromatographed over 15 g
slurry-packed silica gel, eluting with 15% EtOAc/hexane. The
appropriate fractions are combined and concentrated to afford 153
mg (44%) of methyl 3-methyl-1-benzofuran-5-carboxylate as a white
solid. HRMS (FAB) calcd for C.sub.11H.sub.10O.sub.3+H: 191.0708,
found: 191.0705 (M+H).sup.+.
[0672] Methyl 3-methyl-1-benzofuran-5-carboxylate (365 mg, 1.9
mmol) is dissolved in MeOH (7 mL), diluted with H.sub.2O (3.5 mL)
and treated with 3N NaOH (1.41 mL, 4.2 mmol). The mixture is
diluted with MeOH (3.5 mL) to homogeneity, stirred at RT for 2.5
days then concentrated to dryness. The residue is dissolved in
H.sub.2O (5 mL) and acidified to pH 2 with concentrated HCl. The
resulting solid is filtered and dried in a vacuum oven at
40.degree. C. for 18 h to afford 321 mg (95%) of
3-methyl-1-benzofuran-5-carboxylic acid as a white solid. HRMS
(FAB) calcd for C.sub.10H.sub.8O.sub.3+H: 177.0552, found: 177.0553
(M+H).sup.+.
[0673] 3-Methyl-1-benzofuran-5-carboxylic acid (156 mg, 0.88 mmol)
is coupled with (R)-3-aminoquinuclidine dihydrochloride (193 mg,
0.97 mmol) and salt made according to Method A with non-critical
variations to afford 235 mg (83%) of Example 17 as a white solid.
HRMS (FAB) calcd for C.sub.17H.sub.20N.sub.2O.sub.2+H: 285.1603,
found 285.1613 (M+H).sup.+.
EXAMPLE 18
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamid-
e hydrochloride
[0674] 54
[0675] Methyl 4-hydroxy-3-iodobenzoate (6.0 g, 21.5 mmol) is
dissolved in DMF (35 ml) in a dry flask under nitrogen and cooled
to 0.degree. C. NaH (60% dispersion in oil, 860 mg, 21.5 mmol) is
added portion-wise and the reaction is stirred for 1 h, allowing
the ice bath to expire. The mixture is then treated with
1-chloro-3-methyl-2-butene (2.67 ml, 23.7 mmol) and NaI (323 mg,
2.15 mmol), and the reaction is stirred for 18 h at RT. The mixture
is diluted with EtOAc (150 ml) and washed with 1:1 saturated
NaCl/NaHCO.sub.3 (100 ml). The organic layer is dried (MgSO.sub.4),
concentrated to an oil and chromatographed over 700 g slurry-packed
silica gel, eluting with 15% EtOAc/hexane. The appropriate
fractions are collected and concentrated to afford 5.13 g of a pale
oil. The dimethylallyl ether is dissolved in DMF (40 ml) and
treated successively with Pd(OAc).sub.2 (165 mg, 0.74 mmol),
Na.sub.2CO.sub.3 (3.9 g, 36.8 mmol), sodium formate (1.0 g, 14.7
mmol), and n-Bu.sub.4NCl.H.sub.2O (4.5 g, 16.2 mmol). The mixture
is stirred for 2 days at 80.degree. C., then diluted with EtOAc
(200 ml) and washed with 50% saturated NaCl (3.times.75 ml)
followed by 5% HCl (75 ml). The organic layer is dried
(MgSO.sub.4), filtered and concentrated to a brown oil. The crude
material is chromatographed over 250 g slurry-packed silica gel,
eluting with 10% EtOAc/hexane. The appropriate fractions are
collected and concentrated to afford 1.33 g (28% over 2 steps) of
methyl 3-isopropyl-1-benzofuran-5-carboxylate as an oil. HRMS (FAB)
calcd for C.sub.13H.sub.14O.sub.3+H: 219.1021, found 219.1021
(M+H).sup.+.
[0676] Methyl 3-isopropyl-1-benzofuran-5-carboxylate (1.20 g, 5.51
mmol) is dissolved in MeOH (20 ml) and water (4 ml), treated
drop-wise with 2N NaOH (3.3 ml, 6.6 mmol) and stirred at RT for 2
days, then at 40.degree. C. for 4 h. The volatiles are removed in
vacuo, the residue is dissolved in water (10 ml) and the pH is
adjusted to 3 with concentrated HCl. The resulting precipitate is
isolated via filtration and dried overnight to afford 1.08 g (97%)
of 3-isopropyl-1-benzofuran-5-carboxylic acid as a white solid. MS
(ESI-) for C.sub.12H.sub.12O.sub.3 m/z: 203.0 (M-H).sup.-.
[0677] 3-Isopropyl-1-benzofuran-5-carboxylic acid (204 mg, 1.0
mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (219
mg, 1.1 mmol) and salt made according to Method A with non-critical
variations to afford 313 mg (90%) of Example 19 as a white solid.
HRMS (FAB) calcd for C.sub.19H.sub.24N.sub.2O.sub.2+H: 313.1916,
found 313.1913 (M+H).sup.+.
EXAMPLE 19
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide.fumarate
[0678] 55
[0679] 1-Benzofuran-5-carboxylic acid is coupled with
(R)-3-aminoquinuclidine dihydrochloride according to Method C
making non-critical changes to give the free base as a white solid
(1.1 g, 95%) and Example 19 as a white solid (1.5 g, 92%): .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.20, 7.88, 7.85, 7.61, 6.97,
6.70, 4.50-4.43, 3.89-3.80, 3.50-3.23, 2.40-2.34, 2.32-2.21,
2.16-2.08, 2.00-1.89.
EXAMPLE 20
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamide
hydrochloride
[0680] 56
[0681] Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (4.15
g, 16.7 mmol) is dissolved in MeOH (45 ml) and treated with DIA
(2.34 ml, 16.7 mmol). Copper iodide (159 mg, 0.84 mmol) is added
portion-wise and the reaction is heated at 75.degree. C. for 3 h.
DARCO (2 g) is added and the reaction is stirred at 95.degree. C.
for an additional 2 h, then overnight at RT. The reaction is
filtered, concentrated to a brown oil and the crude material is
chromatographed over 300 g slurry-packed silica gel, eluting with
10% EtOAc/hexane. The appropriate fractions are collected and
concentrated to afford 2.05 g (70%) of methyl
1-benzofuran-6-carboxylate as an orange crystalline solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 3.97, 6.84, 7.65, 7.78, 7.98,
8.22 ppm.
[0682] Methyl 1-benzofuran-6-carboxylate (1.90 g, 10.7 mmol) is
dissolved in Et.sub.2O (50 ml) and cooled to 0.degree. C. Chlorine
gas is bubbled in for 5 min, and the reaction is stirred over the
weekend, allowing the ice bath to expire. The volatiles are removed
in vacuo, and the crude material is chromatographed over 300 g
slurry-packed silica gel, eluting with 10% EtOAc/hexane. The
appropriate fractions are collected and concentrated to afford 906
mg (34%) of cis-methyl 2,3-dichloro-2,3-dihydr-
o-1-benzofuran-6-carboxylate as a pale oil. A second pool of
fractions is collected and concentrated to afford 1.25 g (47%) of
trans-methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate
and as a yellow oil.
[0683] trans-isomer: .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
3.93, 5.47, 6.53, 7.56, 7.69, 7.85 ppm.
[0684] cis-isomer: .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 3.94,
5.68, 6.69, 7.49,7.63, 7.85 ppm
[0685] trans-Methyl
2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate (58 mg, 0.23
mmol) is dissolved in EtOH (2 ml), treated with K.sub.2CO.sub.3
(187 mg, 1.35 mmol) and stirred at RT overnight. The mixture is
concentrated to dryness, the residue is dissolved in 50% saturated
NaCl (10 ml) and extracted with CH.sub.2Cl.sub.2 (3.times.10 ml).
The combined organics are dried (K.sub.2CO.sub.3), filtered, and
concentrated in vacuo to a yellow oil. The crude material is
chromatographed over 10 g slurry-packed silica gel, eluting with
25% EtOAc/hexane. The appropriate fractions are combined and
concentrated to afford 30 mg (58%) of ethyl
3-chloro-1-benzofuran-6-carboxylate as a yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 1.44, 4.43, 7.66, 7.79, 8.07, 8.21
ppm.
[0686] Ethyl 3-chloro-1-benzofuran-6-carboxylate (110 mg, 0.49
mmol) is dissolved in MeOH (3 ml) and water (0.75 ml), treated
drop-wise with 2N NaOH (0.27 ml, 0.54 mmol) and stirred overnight
at RT. The volatiles are removed in vacuo, the residue is dissolved
in water (3 ml) and the pH is adjusted to 3 with concentrated HCl.
The resulting solid is filtered and dried overnight in a vacuum
oven to afford 88 mg (92%) of 3-chloro-1-benzofuran-6-carboxylic
acid as a white solid. MS for C.sub.9H.sub.5ClO.sub.3 (ED) m/z:
196(M).sup.+.
[0687] 3-Chloro-1-benzofuran-6-carboxylic acid (75 mg, 0.38 mmol)
is coupled with (R)-3-aminoquinuclidine dihydrochloride (84 mg,
0.42 mmol) and salt made according to Method A with non-critical
variations to afford 116 mg (89%) of Example 20 as an ivory-colored
solid. HRMS (FAB) calcd for C.sub.16H.sub.17ClN.sub.2O.sub.2+H:
305.1057, found 305.1043 (M+H).sup.+.
EXAMPLE 21
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide
[0688] 57
[0689] Methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate (11 g,
44.5 mmol) is combined with DIA (7.1 ml, 50 mmol) and cuprous
iodide (423 mg, 2.2 mmol) in 100 ml MeOH in a flask under nitrogen.
The reaction is warmed to 60.degree. C. for 6 h, the volatiles are
removed in vacuo, and the brown-green residue is chromatographed
over 500 g silica gel (230-400 mesh) eluting with 20% EtOAc/hexane.
The appropriate fractions are combined and concentrated to give
2.63 g (34%) of methyl benzofuran-5-carboxylate as a pale oil which
crystallized on standing. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. 3.95, 6.86, 7.53, 7.70, 8.03, 8.36 ppm.
[0690] Methyl benzofuran-5-carboxylate (1.74 g, 9.9 mmol) is
dissolved in CH.sub.2Cl.sub.2 (50 mL), layered with saturated
NaHCO.sub.3 (75 mL) using very slow magnetic stirring so that the
two layers are not mixed and treated with Br.sub.2 (3.1 mL, 59.1
mmol). The bi-phasic mixture is stirred slowly for 2 h, then
vigorously for 1 h. The layers are separated and the aqueous layer
is extracted with CH.sub.2Cl.sub.2 (2.times.50 mL). The organics
are dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure without heat. The residue is dissolved in MeOH (100 mL),
treated with K.sub.2CO.sub.3 (8.17 g, 59.1 mmol) and stirred at RT
for 18 h. The mixture is concentrated to dryness, partitioned
between 50% saturated NaHCO.sub.3 (75 mL) and EtOAc (2.times.75 mL)
and the organics are dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The crude material (2.21 g) is adsorbed onto silica gel (4.5
g) chromatographed over 90 g slurry-packed silica gel, eluting with
8% EtOAc/hexane then 15% EtOAc/hexane. The appropriate fractions
are combined and concentrated to afford 1.88 g (75%) of methyl
3-bromo-1-benzofuran as a white solid. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 3.99, 7.55, 7.74, 8.11, 8.31 ppm.
[0691] Methyl benzofuran-5-carboxylate (667 mg, 3.8 mmol) is
dissolved in 20 ml CH.sub.2Cl.sub.2 in a flask under nitrogen. The
solution is treated with Br.sub.2 (1.2 ml, 22.8 mmol), is layered
with 20 ml saturated NaHCO.sub.3, and the reaction is stirred
gently for 2 h at RT. The reaction is stirred vigorously for 30
min, the layers are separated, and the organic layer is
concentrated in vacuo to an amber oil. The residue is dissolved in
30 ml EtOH, the solution is treated with anhydrous K.sub.2CO.sub.3
(3.15 g, 22.8 mmol), and the reaction is stirred vigorously
overnight. The insoluble material is removed by filtration and the
filtrate is diluted with 3 ml 3N NaOH and the mixture is stirred 3
h at RT. The mixture is concentrated in vacuo, the residue is
dissolved in 10 ml H.sub.2O, and the pH of the solution is adjusted
to 2 with 10% aqueous HCl. The precipitate is collected, washed
with water, and is dried to afford 880 mg (96%) of
3-bromobenzofuran-5-carboxylic acid as an off-white solid. HRMS
(FAB) calcd for C.sub.9H.sub.5BrO.sub.3+H: 240.9501, found 240.9505
(M+H).sup.+.
[0692] 3-Bromo-1-benzofuran-5-carboxylic acid (241 mg, 1.0 mmol) is
coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1
mmol) according to Method A to afford 280 mg (80%) of Example 21 as
an off-white solid. HRMS (ESI) calcd for
Cl.sub.6H.sub.17BrN.sub.2O.sub.2+H: 349.0552, found 349.0555
(M+H).sup.+.
EXAMPLE 22
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide
[0693] 58
[0694]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxa-
mide (350 mg, 1.0 mmol) is combined with bis(benzonitrile)palladium
dichloride (57 mg, 0.15 mmol), cuprous iodide (19 mg, 0.10 mmol),
tri(t-butyl)phosphine (658 .mu.L, 0.325 mmol),
trimethylsilylacetylene (170 .mu.L, 1.2 mmol), and DIA (168 .mu.L,
1.2 mmol) in dioxane (3 ml) in a dry flask under nitrogen. The
reaction is stirred overnight at RT, is diluted with EtOAc (25 ml),
is washed with 1:1:0.1 NaCl/water/conc. NH40H (4.times.25 ml), and
the organic layer is dried (K.sub.2CO.sub.3). The volatiles are
removed in vacuo and the residue is chromatographed over 30 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 afford 268 mg (73%) of
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-[(trimethyl-
silyl)ethynyl]-1-benzofuran-5-carboxamide as a pale foam. HRMS
(ESI) calcd for C.sub.21H.sub.26N.sub.2O.sub.2SI+H: 367.1841, found
367.1852 (M+H).sup.+.
[0695]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-[(trimethylsilyl)ethynyl]-1--
benzofuran-5-carboxamide (255 mg, 0.70 mmol) is dissolved in MeOH
(6 ml). The solution is treated with saturated NaHCO.sub.3 (2 ml)
and the reaction is stirred overnight at RT. The volatiles are
removed in vacuo and the residue is chromatographed over 30 g
silica gel (230-400 mesh) eluting with 8% MeOH/CHCl.sub.3+1% conc.
NH.sub.4OH. The appropriate fractions are combined and concentrated
to give 190 mg of a yellow foam. The foam is crystallized from
Et.sub.2O to provide 138 mg (67%) of Example 22 as a pale yellow
solid. HRMS (ESI) calcd for C.sub.18H.sub.18N.sub.2O.sub.2 +H:
295.1446, found 295.1458 (M+H).sup.+.
EXAMPLE 23
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxam-
ide
[0696] 59
[0697] Methyl 3-bromobenzofuran-5-carboxylate (750 mg, 2.94 mmol)
is combined with bis(benzonitrile)palladium dichloride (169 mg,
0.44 mmol), cuprous iodide (19 mg, 0.10 mmol), tri-t-butylphosphine
((10% in hexane) 1.92 ml, 0.95 mmol), and propyne (2 ml, 35 mmol)
in 7 ml dry dioxane in 15 ml screw cap pressure tube under
nitrogen. The mixture is treated with DIA (494 .mu.L, 3.6 mmol), is
stirred overnight at RT, and is diluted with 50 ml EtOAc. The
reaction is washed with 4.times.25 ml 1:1:0.1 H.sub.2O/brine/conc.
NH.sub.4OH, the organic layer is dried (MgSO.sub.4), and the
volatiles are removed in vacuo. The crude material is
chromatographed over 50 g silica gel (230-400 mesh) eluting with
12% EtOAc/hexane. The appropriate fractions are combined and
concentrated to give 460 mg (73%) of methyl
3-prop-1-ynyl-1-benzofuran-5-carboxylate as a pale solid. MS for
C.sub.13H.sub.10O.sub.3 (EI) m/z (rel. intensity): 214
(M).sup.+.
[0698] Methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate (388 mg,
1.81 mmol) is dissolved in 10 ml MeOH. The solution is treated with
2N NaOH (2.3 ml, 4.6 mmol) followed by 2 ml H.sub.2O and the
reaction is stirred overnight at RT. The reaction is concentrated
to dryness, the residue is dissolved in 9 ml H.sub.2O, and the pH
is adjusted to 3 with 10% aqueous HCl. The precipitate is
collected, washed with H.sub.2O, and is dried to afford 356 mg
(98%) of 3-prop-1-ynyl-1-benzofuran-5-carboxylic acid as an
off-white solid. HRMS (EI) calcd for C.sub.12H.sub.8O.sub.3:
200.0473, found 200.0476 (M.sup.+).
[0699] 3-Prop-1-ynyl-1-benzofuran-5-carboxylic acid (178 mg, 1.0
mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (219
mg, 1.1 mmol) according to Method A to afford 200 mg (65%) of
Example 23 as an off-white solid. HRMS (ESI) calcd for
C.sub.19H.sub.20N.sub.2O.sub.2+H: 309.1603, found 309.1599
(M+H).sup.+.
EXAMPLE 24
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide.fu-
marate
[0700] 60
[0701] A mixture of ethyl and methyl
3-bromo-1-benzofuran-5-carboxylate (778 mg, 3.0 mmol) is combined
with zinc cyanide (211 mg, 1.8 mmol),
tris(dibenzylideneacetone)dipalladium (110 mg, 0.12 mmol),
1,1'-bis(diphenylphosphino)ferrocene (132 mg, 0.24 mmol) and zinc
dust (46 mg, 0.72 mmol) in a dry flask under nitrogen. The vessel
is purged with nitrogen, treated with dimethyl acetamide (6 mL) and
heated to 120.degree. C. for 18 h. The mixture is cooled to RT
diluted with EtOAc (50 mL), filtered through celite and washed with
2N NH.sub.4OH (2.times.50 mL). The organics are further washed with
NaCl (50 mL), dried (Na.sub.2SO.sub.4) and concentrated to a brown
solid (763 mg). The crude material is chromatographed over 30 g
slurry-packed silica gel, eluting with 12% EtOAc/hexane. The
appropriate fractions are combined and concentrated to afford 280
mg (45%) of the mixed methyl and ethyl esters as a yellow solid
(45% ethyl ester/55% methyl ester). The mixture of ethyl and methyl
3-cyano-1-benzofuran-5-carboxylate (270 mg, 1.3 mmol) is suspended
in pH 7 buffer (11 mL), treated with a solution of pig liver
esterase (64 mg) in pH 7 buffer (4 mL) and stirred vigorously at RT
for 16 h. Acetone (2 mL) is added, the mixture is stirred for 24 h
and filtered through celite. The filtrate is acidified to pH 2 with
concentrated HCl. The resulting solid is stirred for 45 min,
filtered and dried in a vacuum oven at 80.degree. C. for 16 h to
afford 100 mg (41%) of 3-cyano-1-benzofuran-5-carboxylic acid as a
white solid. MS for C.sub.10H.sub.5NO.sub.3, (EI) m/z: 187
(M).sup.+.
[0702] 3-Cyano-1-benzofuran-5-carboxylic acid (94 mg, 0.5 mmol) is
coupled with (R)-3-aminoquinuclidine dihydrochloride (109 mg, 0.55
mmol) according to Method A. The free base (123 mg) is combined
with fumaric acid (48 mg, 0.41 mmol) in MeOH (0.7 mL) and the
fumarate salt is precipitated upon addition of EtOAc (7 ml). The
solid is collected, rinsed with Et.sub.2O, and dried in a vacuum
oven at 60.degree. C. to afford 126 mg (61%) of Example 24 as a
white solid. HRMS (FAB) calcd for C.sub.17H.sub.17N.sub.3O.sub.2+H:
296.1399, found 296.1403 (M+H).sup.+.
EXAMPLE 25
N-5-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarboxamide
[0703] 61
[0704]
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxa-
mide (148 mg, 0.5 mmol) is dissolved in conc. H.sub.2SO.sub.4 (0.5
mL, 18 mmol) and water (50 .mu.L) and stirred at RT for 4.5 h. The
pH is adjusted to 12 with 10N NaOH and the resulting solid filtered
and rinsed with acetone. The filtrate is extracted with 10%
MeOH/CHCl.sub.3 (6.times.20 mL) and the organics are dried
(Na.sub.2SO.sub.4) and concentrated to a white foam (173 mg). The
foam is triturated with Et.sub.2O, the resulting solid filtered,
and dried in a vacuum oven at 50.degree. C. to afford 99 mg (63%)
of Example 25 as an off-white solid. HRMS (ESI) calcd for
C.sub.17H.sub.19N.sub.3O.sub.3+H: 314.1505, found 314.1502
(M+H).sup.+.
EXAMPLE 26
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamide
hydrochloride
[0705] 62
[0706] 1-Benzofuran-5-carboxylic acid (0.177 g) is coupled with
(3R,5R)-[3.2.1]-Amine (0.221 g) using Method A, making non-critical
changes to afford 0.267 g of Example 26 as an off-white foam:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.67, 8.50-8.60, 8.32;
8.18, 7.82, 7.69, 7.08, 4.40-4.60, 3.05-3.60, 2.65-2.75, 2.05-2.20,
1.85-2.00.
EXAMPLE 27
N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide.fumarat-
e
[0707] 63
[0708] 1-Benzofuran-5-carboxylic acid (0.762 g) is coupled with
(3R,5R)-[3.2.1]-Amine (0.620 g) using Method A, making non-critical
changes. The free base is treated with EtOH/fumaric acid, heated,
partially evaporated, collected by filtration and dried in vaccuo
to afford 0.477 g of Example 27 as an off-white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.30-8.40, 8.10-8.15, 8.08,
7.70-7.80, 7.00-7.05, 6.51, 4.30-4.45, 3.00-3.45, 2.75-2.95,
1.65-2.00.
EXAMPLE 28
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-5-carboxamide
[0709] 64
[0710] Method B
[0711] To a stirred solution of 1H-indole-5-carboxylic acid (80.6
mg, 0.5 mmol) in DMF (10 mL) are added DIEA (265 .mu.L, 1.52 mmol)
and exo-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is cooled to
0.degree. C. in an ice bath, and HATU (190 mg, 0.5 mmol) is added
in one portion. The reaction mixture is allowed to warm to RT and
stirs for 2 days. The solvent is removed in vacuo and the residue
is partitioned between saturated aqueous K.sub.2CO.sub.3 solution
and chloroform-methanol (95:5). The aqueous layer is extracted with
chloroform-methanol (95:5) twice. 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 (90:9:1) gives 90 mg (71%) of Example
28 as a white solid: .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.13, 7.62, 7.44, 7.33, 6.56, 3.84-3.81, 3.37, 3.09-3.04,
2.86-2.75, 2.69, 2.60-2.53, 2.45, 1.81-1.72, 1.41-1.34.
EXAMPLE 29
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide.fumarate
[0712] 65
[0713] Method C
[0714] To a stirred solution of 1H-indole-6-carboxylic acid (81 mg,
0.5 mmol) in anhydrous DMF (10 mL) are added DEEA (265 .mu.L, 1.52
mmol) and exo-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is
cooled to 0.degree. C., and HATU (190 mg, 0.5 mmol) is added in one
portion. The reaction mixture is allowed to warm to RT and stirs
overnight. The solvent is removed in vacuo and the residue is
partitioned between saturated aqueous K.sub.2CO.sub.3 solution and
chloroform. The aqueous layer is extracted with chloroform
(2.times.). The combined organic layers are washed with brine,
dried (Na.sub.2SO.sub.4), 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 free
base as a yellow solid (84 mg, 66%).
[0715] To a stirred solution of the free base (84 mg, 0.33 mmol) in
methanol (5 mL) is added a warm solution of fumaric acid (38 mg,
0.33 mmol) in methanol (5 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 (5 mL). The mixture is stirred
overnight at RT. The solid is collected by filtration, washed with
acetone, and dried under high vacuum overnight to give 88 mg (72%)
of Example 29 as a white solid: .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 11.38, 8.32-8.31, 7.94, 7.58-7.50, 6.54, 6.48, 3.86-3.82,
3.15-3.10, 2.97-2.89, 2.67-2.55, 1.78-1.69, 1.38-1.31.
EXAMPLE 30
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide.fumar-
ate
[0716] 66
[0717] 1-Benzofuran-6-carboxylic acid is coupled with
exo-[2.2.1]-Amine according to Method C making non-critical changes
to give the free base as a yellow solid (237 mg, 91%) and Example
30 as a white solid (307 mg, 89%): .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.07, 7.95-7.94, 7.81-7.72, 6.96-6.95, 6.71,
4.27-4.25, 3.75-3.69, 3.47-3.36, 3.27-3.22, 3.08-3.07, 2.23-2.14,
1.89-1.81.
EXAMPLE 31
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-6-carboxamide.f-
umarate
[0718] 67
[0719] 1-Benzothiophene-6-carboxylic acid is coupled with
exo-[2.2.1]-Amine according to Method C, allowing the reaction to
stir for 3 days and making non-critical changes to give the free
base as a white solid (272 mg, 100%). The salt is obtained
according to Method C, stirring the reaction at 40.degree. C. for
10 min to afford Example 31 as a white solid (333 mg, 86%): .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.47, 7.96, 7.86, 7.81, 7.48,
6.71, 4.27-4.24, 3.74-3.68, 3.46-3.35, 3.26-3.20, 3.07, 2.22-2.13,
1.87-1.81.
EXAMPLE 32
N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-6-carboxami-
de.fumarate
[0720] 68
[0721] 3-Bromo-1-benzofuran-6-carboxylic acid is coupled with
exo-[2.2.1]-Amine according to Method C, allowing the reaction to
stir for 2 days and making non-critical changes to give the free
base as a light yellow oil (287 mg, 100%). The salt is obtained
according to Method C, stirring the reaction at 40.degree. C. for
10 min to afford Example 32 as a white solid (303 mg, 80%): .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.15, 8.06, 7.96, 7.67, 6.71,
4.28-4.26, 3.75-3.70, 3.49-3.37, 3.28-3.23, 3.08, 2.23-2.15,
1.89-1.82.
EXAMPLE 33
N-[(exo-4R)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.fumar-
ate
[0722] 69
[0723] 1-Benzofuran-5-carboxylic acid is coupled with
exo-(4R)-[2.2.1]-Amine according to Method C, allowing the reaction
to stir for 2 days and making non-critical changes to give the free
base as a yellow solid (510 mg, 100%). The salt is obtained
according to Method C, stirring the reaction at 40.degree. C. for
30 min to afford Example 33 as a white solid (670 mg, 90%): .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.19, 7.89-7.75, 7.61, 6.97,
6.71, 4.26-4.23, 3.73-3.68, 3.45-3.35, 3.26-3.20, 3.07, 2.21-2.13,
1.88-1.80.
EXAMPLE 34
N-[(endo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.fuma-
rate and
N-[(endo-4R)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxa-
mide.fumarate
[0724] 70
[0725] 1-Benzofuran-5-carboxylic acid is coupled with racemic
endo-[2.2.1]-Amine according to Method C, stirring for 2 days,
making non-critical changes to afford the free base as a recemic
mixture (440 mg, 98%). The racemic product is resolved by chiral
chromatography using a Chiralcel OJ column to afford 190 mg (43%)
of the (-)-enantiomer and 160 mg (36%) of the (+)-enantiomer. The
fumarate salts of both enantimers are made according to Method C,
making non-critical changes. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.21, 7.89-7.85, 7.62, 6.98, 6.71, 4.70-4.65, 3.88-3.82,
3.51-3.35, 3.29-3.27, 3.16-3.11, 2.23-2.16, 2.14-2.05.
EXAMPLE 35
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamid-
e hydrochloride
[0726] 71
[0727] 1-Benzofuran-6-carboxylic acid (0.16 g, 1.0 mmol), HATU
(0.46 g, 1.2 mmol) and 2S-methyl-2.2.2-Amine (0.213 g, 1.0 mmol)
are dissolved in 12 mL CH.sub.3CN. DIEA (1.4 mL, 8.0 mmol) is added
dropwise. After 3 days, 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 203 mg (63%) of the product. HRMS (FAB)
calculated for C.sub.17H.sub.20N.sub.2O.sub.2+H=285.1- 603, found
285.1617.
EXAMPLE 36
N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carbox-
amide hydrochloride
[0728] 72
[0729] 1-Benzothiophene-5-carboxylic acid is coupled with
2S-methyl-2.2.2-Amine and the hydrochloride salt is prepared
following the procedure of Example 35, making non-critical changes
to afford Example 36 (137 mg, 73%). HRMS (FAB) calculated for
C.sub.17H.sub.20N.sub.2OS+H 301.1375, found 301.1380.
EXAMPLE 37
N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide.0.5fumarat-
e
[0730] 73
[0731] 1-benzofuran-5-carboxylic acid is coupled with
3(R)-[3.2.2]-Amine according to Method C making non-critical
changes to give the free base as a white solid (220 mg, 77%) and
Example 37 as a white solid (90 mg, 66%): .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.16, 7.88, 7.82, 7.60, 6.97, 6.69, 4.75-4.65,
3.70, 3.50-3.41, 3.41-3.20, 3.04, 2.48-2.33, 2.14-1.93, 1.87.
Materials and Methods for Determining .alpha.7 nAChR Agonist
Activity
[0732] Cell-Based Assay for Measuring the EC.sub.50 of .alpha.7
nAChR Agonists
[0733] Construction and Expression of the .alpha.7-5HT.sub.3
Receptor:
[0734] The cDNA encoding the N-terminal 201 amino acids from the
human .alpha.7 nAChR that contain the ligand binding domain of the
ion channel was fused to the cDNA encoding the pore forming region
of the mouse 5HT.sub.3 receptor as described by Eisele J L, et al.,
Chimaeric nicotinic-serotonergic receptor combines distinct ligand
binding and channel specificities, Nature (1993), December
2;366(6454):479-83, and modified by Groppi, et al., WO 00/73431.
The chimeric .alpha.7-5HT.sub.3 ion channel was inserted into pGS
175 and pGS 179 which contain the resistance genes for G-418 and
hygromycin B, respectively. Both plasmids were simultaneously
transfected into SH-EP1 cells and cell lines were selected that
were resistant to both G-418 and hyrgromycin B. Cell lines
expressing the chimeric ion channel were identified by their
ability to bind fluorescent .alpha.-bungarotoxin on their cell
surface. The cells with the highest amount of fluorescent
.alpha.-bungarotoxin binding were isolated using a Fluorescent
Activated Cell Sorter (FACS). Cell lines that stably expressed the
chimeric .alpha.7-5HT.sub.3 were identified by measuring
fluorescent .alpha.-bungarotoxin binding after growing the cells in
minimal essential medium containing nonessential amino acids
supplemented with 10% fetal bovine serum, L-glutamine, 100 units/ml
penicillin/streptomycin, 250 ng/mg fungizone, 400 .mu.g/ml
hygromycin B, and 400 .mu.g/ml G-418 at 37.degree. C. with 6%
CO.sub.2 in a standard mammalian cell incubator for at least 4
weeks in continuous culture.
[0735] Assay of the Activity of the Chimeric .alpha.7-5HT.sub.3
Receptor
[0736] To assay the activity of the .alpha.7-5HT.sub.3 ion channel,
cells expressing the channel were plated into each well of either a
96 or 384 well dish (Corning #3614) and grown to confluence prior
to assay. On the day of the assay, the cells were loaded with a 1:1
mixture of 2 mM Calcium Green 1, AM (Molecular Probes) dissolved in
anhydrous DMSO and 20% pluronic F-127 (Molecular Probes). This
solution was added directly to the growth media of each well to
achieve a final concentration 2 .mu.M. The cells were incubated
with the dye for 60 min at 37.degree. C. and then washed with a
modified version of Earle's balanced salt solution (MMEBSS) as
described in WO 00/73431. The ion conditions of the MMEBSS was
adjusted to maximize the flux of calcium ion through the chimeric
.alpha.7-5HT.sub.3 ion channel as described in WO 00/73431. The
activity of compounds on the chimeric .alpha.7-5HT.sub.3 ion
channel was analyzed on FLIPR. The instrument was set up with an
excitation wavelength of 488 nanometers using 500 milliwatts of
power. Fluorescent emission was measured above 525 nanometers with
an appropriate F-stop to maintain a maximal signal to noise ratio.
Agonist activity of each compound was measured by directly adding
the compound to cells expressing the chimeric .alpha.7-5HT.sub.3
ion channel and measuring the resulting increase in intracellular
calcium that is caused by the agonist-induced activation of the
chimeric ion channel. The assay is quantitative such that
concentration-dependent increase in intracelluar calcium is
measured as concentration-dependent change in Calcium Green
fluorescence. The effective concentration needed for a compound to
cause a 50% maximal increase in intracellular calcium is termed the
EC.sub.50. The examples were tested and have EC.sub.50 values from
about 25 nM to about 10,000 nM:
[0737] Binding Constants:
[0738] Another way for measuring .alpha.7 nAChR agonist activity is
to determine binding constants of a potential agonist in a
competition binding assay. For .alpha.7 nAChR agonists, there is
good correlation between functional EC.sub.50 values using the
chimeric .alpha.7-5HT.sub.3 ion channel as a drug target and
binding affinity of compounds to the endogenous .alpha.7 nAChR.
[0739] Membrane Preparation.
[0740] 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 0.32 M 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 rt and diluted with Kreb's--20 mM
Hepes buffer pH 7.0 (at rt) 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 ,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.
[0741] Binding Assay.
[0742] 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 hour at
25.degree. C. Nonspecific binding was determined in tissues
incubated in parallel in the presence of 0.05 mls MLA for a final
concentration of 1 .mu.M, added before the radioligand. In
competition studies, drugs are added in increasing concentrations
to the test tubes before addition of 0.05 mls [.sup.3H]-MLA for a
final concentration 3.0 to 4.0 nM. 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.
[0743] Data Analysis.
[0744] In competition binding studies, the inhibition constant (Ki)
was calculated from the concentration dependent inhibition of
[.sup.3 H]-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, p. 3099-3108, 1973). Hill
coefficients were obtained using non-linear regression (GraphPad
Prism sigmoidal dose-response with variable slope).
* * * * *