U.S. patent application number 12/551020 was filed with the patent office on 2010-01-21 for nicotinic alpha-7 receptor ligands and preparation and uses thereof.
Invention is credited to Brian Herbert, Truc Minh Nguyen, Richard Schumacher, Ashok Tehim, Wenge Xie.
Application Number | 20100016351 12/551020 |
Document ID | / |
Family ID | 36177987 |
Filed Date | 2010-01-21 |
United States Patent
Application |
20100016351 |
Kind Code |
A1 |
Nguyen; Truc Minh ; et
al. |
January 21, 2010 |
NICOTINIC ALPHA-7 RECEPTOR LIGANDS AND PREPARATION AND USES
THEREOF
Abstract
The present invention relates generally to the field of ligands
for nicotinic acetylcholine receptors (nAChR), activation of
nAChRs, and the treatment of disease conditions associated with
defective or malfunctioning nicotinic acetylcholine receptors,
especially of the brain. Further, this invention relates to novel
compounds which act as ligands for the .alpha.7 nAChR subtype,
methods of preparing such compounds, compositions containing such
compounds, and methods of use thereof.
Inventors: |
Nguyen; Truc Minh; (New
York, NY) ; Xie; Wenge; (Mahwah, NJ) ;
Schumacher; Richard; (Monroe, NY) ; Herbert;
Brian; (Stockholm, NJ) ; Tehim; Ashok;
(Ridgewood, NJ) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
36177987 |
Appl. No.: |
12/551020 |
Filed: |
August 31, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11312831 |
Dec 21, 2005 |
7625924 |
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12551020 |
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60637771 |
Dec 22, 2004 |
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Current U.S.
Class: |
514/305 ;
546/133 |
Current CPC
Class: |
A61P 25/34 20180101;
A61P 25/28 20180101; A61P 25/18 20180101; A61P 25/16 20180101; A61P
3/10 20180101; A61P 25/24 20180101; A61P 31/04 20180101; A61P 25/00
20180101; C07D 453/02 20130101; A61P 25/22 20180101; A61P 29/00
20180101; A61P 9/00 20180101; A61P 25/02 20180101; A61P 43/00
20180101; A61P 25/04 20180101; A61P 3/04 20180101; A61P 21/00
20180101; A61P 25/14 20180101; A61P 25/32 20180101 |
Class at
Publication: |
514/305 ;
546/133 |
International
Class: |
A61K 31/4375 20060101
A61K031/4375; C07D 453/02 20060101 C07D453/02 |
Claims
1. A compound according to Formula I: ##STR00040## wherein X.sup.1
to X.sup.4 are each, independently, N or CR.sup.1, wherein at most
one of X.sup.1 to X.sup.4 is N; B is --C(O)--NH--CH.sub.2--; Y is
O, S, or NH; R.sup.1 is H, C.sub.1-4-alkyl, or C.sub.2-4-alkenyl,
which, in each case is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof,
C.sub.2-4-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations, C.sub.1-4-alkoxy which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.2,
NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations
thereof, Ar, Het, halogen, CN, NO.sub.2, NR.sup.3R.sup.4, SR.sup.4,
SOR.sup.4, SO.sub.2R.sup.4, SO.sub.2NR.sup.3R.sup.4,
NR.sup.3SO.sub.2R.sup.4, CONR.sup.3R.sup.4, CSNR.sup.3R.sup.4,
COOR.sup.4, NR.sup.3COR.sup.4, NR.sup.3CSR.sup.4,
NR.sup.3CONR.sup.3R.sup.4, NR.sup.3CSNR.sup.3R.sup.4,
NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4, OCONR.sup.3R.sup.4, or
OCSNR.sup.3R.sup.4; R.sup.2 is H, C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl, or C.sub.4-8-cycloalkylalkyl, which, in each
case, is unsubstituted or substituted one or more by F, Cl, Br, I,
CN, OH, alkoxy having 1 to 4 carbon atoms, NR.sup.3R.sup.4, SH,
SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof; R.sup.3
and R.sup.4 are each independently H, C.sub.1-6-alkyl or
C.sub.3-6-alkenyl, which, in each case, is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1
to 6 carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
C.sub.3-6-alkynyl which is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl,
Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or combinations thereof,
C.sub.3-8-cycloalkyl which is unsubstituted or substituted one or
more times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, and/or substituted in the alkyl
portion one or more times by one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations, Ar,
or Het; Ar is an aryl group containing 6 to 10 carbon atoms which
is unsubstituted or substituted one or more times by alkyl having 1
to 8 C carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl
having 2 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms,
cycloalkylalkyl having 4 to 10 carbon atoms, alkoxy having 1 to 8
carbon atoms, halogen, amino, cyano, hydroxyl, nitro, halogenated
alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8
carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8
carbon atoms, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, cycloalkylamino wherein the cycloalkyl portion has 3 to 7
carbon atoms, cycloalkylalkylamino wherein the cycloalkylalkyl
portion has 4 to 8 carbon atoms, carboxy, alkoxycarbonyl,
alkylaminocarbonyl, acylamido, acyloxy, alkylthio having 1 to 8
carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms, sulfo, sulfonylamino,
aryl containing 6 to 10 carbon atoms which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, heterocyclic group which is fully saturated, partially
saturated or fully unsaturated, having 5 to 10 ring atoms in which
at least 1 ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, or combinations thereof; and Het is a heterocyclic group
which is fully saturated, partially saturated or fully unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, O
or S atom, which is unsubstituted or substituted one or more times
by alkyl having 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon
atoms, alkynyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 8
carbon atoms, cycloalkylalkyl having 4 to 10 carbon atoms, alkoxy
having 1 to 8 carbon atoms, halogen, amino, cyano, hydroxyl, nitro,
halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy
having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon
atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having
3 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, cycloalkylamino wherein the cycloalkyl portion has 3 to 7
carbon atoms, cycloalkylalkylamino wherein the cycloalkylalkyl
portion has 4 to 8 C atoms, carboxy, alkoxycarbonyl,
alkylaminocarbonyl, acylamido, acyloxy, alkylthio having 1 to 8
carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms, sulfo, sulfonylamino,
aryl containing 6 to 10 carbon atoms which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, heterocyclic group which is fully saturated, partially
saturated or fully unsaturated, having 5 to 10 ring atoms in which
at least 1 ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, or combinations thereof; or a pharmaceutically acceptable
salt thereof.
2. A compound according to claim 1, wherein R.sup.1 is H, CH.sub.3,
C.sub.2H.sub.5, CF.sub.3, C.sub.2H.sub.3, or C.sub.3H.sub.5, which
in each case is unsubstituted or substituted one or more times by
F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof, C.sub.2H
or C.sub.3H.sub.3, which in each case is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.2,
NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4,
Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or combinations thereof,
OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3, or OCHF.sub.2, which in each
case is unsubstituted or substituted one or more times by F, Cl,
Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar,
Het, or combinations thereof, Ar, Het, F, Cl, Br, I, CN, NO.sub.2,
NR.sup.3R.sup.4, SR.sup.4, SOR.sup.4, SO.sub.2R.sup.4,
SO.sub.2NR.sup.3R.sup.4, NR.sup.3SO.sub.2R.sup.4,
CONR.sup.3R.sup.4, CSNR.sup.3R.sup.4, COOR.sup.4,
NR.sup.3COR.sup.4, NR.sup.3CSR.sup.4, NR.sup.3CONR.sup.3R.sup.4,
NR.sup.3CSNR.sup.3R.sup.4, NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4,
OCONR.sup.3R.sup.4, or OCSNR.sup.3R.sup.4; R.sup.2 is H, CH.sub.3,
C.sub.2H.sub.5, CF.sub.3, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentylmethyl, or cyclopropylmethyl, which, in each case, is
unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof; R.sup.3
and R.sup.4 are each independently H, CH.sub.3, C.sub.2H.sub.5,
CF.sub.3, C.sub.2H.sub.3, or C.sub.3H.sub.5, which, in each case,
is unsubstituted or substituted one or more times by F, Cl, Br, I,
CN, alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, C.sub.2H or C.sub.3H.sub.3, which in each case is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Si(C.sub.1-6-alkyl).sub.3, Ar,
Het, or combinations thereof, cyclopropyl, cyclobutyl, or
cyclopentyl, which in each case is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon
atoms, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
cyclopentylmethyl or cyclopropylmethyl, which in each case is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, and/or substituted in the alkyl
portion one or more times by one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, Ar, or Het; Ar is phenyl, naphthyl or biphenyl, which in
each case is unsubstituted or substituted one or more times by
halogen, alkyl having 1 to 8 carbon atoms, hydroxy, alkoxy having 1
to 8 carbon atoms, nitro, amino, monoalkylamino having 1 to 8 C
atoms, dialkylamino wherein the alkyl portions each have 1 to 8 C
atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy
having 1 to 8 carbon atoms, carboxy, cyano, alkoxycarbonyl 2 to 9
carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl
having 1 to 8 C atoms, alkylsulphonyl having 1 to 8 carbon atoms,
phenoxy, acetoxy, or combinations thereof; and Het is furyl,
thienyl, bithienyl, benzylprazolyl, thiazolyl, imidazolyl,
methylimidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
dihydropyranyl, or tetrahydropyranyl, which in each case is
unsubstituted or substituted one or more times by halogen, alkyl
having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon
atoms, nitro, amino, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy
having 1 to 8 C atoms, carboxy, cyano, alkoxycarbonyl 2 to 9 carbon
atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having
1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms,
phenoxy, acetoxy, or combinations thereof.
3. (canceled)
4. A compound according to claim 1, wherein said compound is of
formula IB: ##STR00041## wherein Y is NH or S; or a
pharmaceutically acceptable salt thereof.
5. A compound according to claim 1, wherein X.sup.1 is CH.
6. A compound according to claim 1, wherein X.sup.2 is CH or
CR.sup.1 in which R.sup.1 is Het, C.sub.1-4-alkoxy, or substituted
C.sub.1-4-alkoxy.
7. A compound according to claim 1, wherein X.sup.2 is CH or
CR.sup.1 in which R.sup.1 is thiazolyl, alkyl substituted
thiazolyl, tetrahydropyranyl, dihydropyranyl, --OCH.sub.3,
--OCF.sub.3 or OCHF.sub.2.
8. A compound according to claim 1, wherein X.sup.3 is CH or
CR.sup.1 in which R.sup.1 is Het, C.sub.1-4-alkoxy, or substituted
C.sub.1-4-alkoxy.
9. A compound according to claim 1, wherein X.sup.3 is CH or
CR.sup.1 in which R.sup.1 is thiazolyl, alkyl substituted
thiazolyl, tetrahydropyranyl, dihydropyranyl, --OCH.sub.3,
--OCF.sub.3 or OCHF.sub.2.
10. A compound according to claim 1, wherein X.sup.4 is CH or
CR.sup.1 in which R.sup.1 is substituted or unsubstituted
C.sub.1-4-alkoxy.
11. A compound according to claim 1, wherein X.sup.4 is CH or
CR.sup.1 in which R.sup.1 is --OCF.sub.3 or OCHF.sub.2.
12. A compound according to claim 1, wherein X.sup.1 to X.sup.4 are
each CH or CR.sup.1 wherein R.sup.1 is not H.
13. A compound according to claim 1, wherein X.sup.1 and X.sup.4
are each CH.
14. A compound according to claim 1, wherein X.sup.2 is CR.sup.1
wherein R.sup.1 is not H, and X.sup.1, X.sup.3, and X.sup.4 are
each CH.
15. A compound according to claim 14, wherein R.sup.1 is thiazolyl,
alkyl substituted thiazolyl, tetrahydropyranyl, dihydropyranyl,
--OCH.sub.3, --OCF.sub.3 or OCHF.sub.2.
16. A compound according to claim 1, wherein X.sup.3 is CR.sup.1
wherein R.sup.1 is not H, and X.sup.1, X.sup.2, and X.sup.4 are
each CH.
17. A compound according to claim 16, wherein R.sup.1 is thiazolyl,
alkyl substituted thiazolyl, tetrahydropyranyl, dihydropyranyl,
--OCH.sub.3, --OCF.sub.3 or OCHF.sub.2.
18. A compound according to claim 1, wherein X.sup.4 is CR.sup.1
wherein R.sup.1 is not H, and X.sup.1, X.sup.2, and X.sup.3 are
each CH.
19. A compound according to claim 18, wherein X.sup.4 is CH or
CR.sup.1 in which R.sup.1 is --OCF.sub.3 or OCHF.sub.2.
20. (canceled)
21. (canceled)
22. A compound according to claim 1, wherein Y is NH or S.
23. A compound according to claim 22, wherein Y is NH.
24. A compound according to claim 1, wherein said compound is
selected from:
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazol-
e-3-carboxamide,
N-1-(Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide-
, and pharmaceutically acceptable salts thereof.
25. A compound according to claim 24, wherein said compound is in
the form of a hydroformate salt or the 4-methylbenzenesulfonate
salt.
26. A compound according to claim 25, wherein said compound is
selected from:
N-1-(Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazol-
e-3-carboxamide hydroformate, and
N-1-(Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide
hydroformate.
27. (canceled)
28. (canceled)
29. (canceled)
30. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound according to Formula I:
##STR00042## wherein X.sup.1 to X.sup.4 are each, independently, N
or CR.sup.1, wherein at most one of X.sup.1 to X.sup.4 is N; B is
--C(O)--NH--CH.sub.2--; Y is O, S, or NH; R.sup.1 is H,
C.sub.1-4-alkyl, or C.sub.2-4-alkenyl, which, in each case is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.2, NR.sup.3R.sup.4SH, SR.sup.3, SOR.sup.3,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar,
Het, or combinations thereof, C.sub.2-4-alkynyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8R.sup.3-cycloalkyl, SO.sub.2R.sup.3
.sub.2NR.sup.3R.sup.4Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations, C.sub.1-4-alkoxy which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.2,
NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations
thereof, Ar Het halogen, CN, NO.sub.2, NR.sup.3R.sup.4, SR.sup.4,
SOR.sup.4, SO.sub.2NR.sup.3R.sup.4, NR.sup.3SO.sub.2R.sup.4,
CONR.sup.3R.sup.4CSNR.sup.3R.sup.4, COOR.sup.4, NR.sup.3COR.sup.4,
NR.sup.3CSR.sup.4, NR.sup.3CONR.sup.3R.sup.4,
NR.sup.3CSNR.sup.3R.sup.4, NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4,
OCONR.sup.3R.sup.4, or OCSNR.sup.3R.sup.4; R.sup.2 is H,
C.sub.1-6-alkyl, C.sub.3-8-cycloalkyl, or
C.sub.4-8-cycloalkylalkyl, which, in each case, is unsubstituted or
substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to
4 carbon atoms, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8cycloalkyl, SO.sub.2NR.sup.3R.sup.4, Ar, Het, or
combinations thereof; R.sup.3 and R.sup.4 are each independently H,
C.sub.1-6-alkyl or C.sub.3-6alkenyl, which, in each case, is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, C.sub.3-6-alkynyl which is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon
atoms, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations thereof, C.sub.3-8-cycloalkyl which is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, alkoxy having
1 to 6 carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof,
C.sub.4-10-cycloalkylalkyl which is unsubstituted or substituted in
the cycloalkyl portion one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8cycloalkyl, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6
carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations, Ar, or Het; Ar is
an aryl group containing 6 to 10 carbon atoms which is
unsubstituted or substituted one or more times by alkyl having 1 to
8 C carbon atoms, alkenyl having 2 to 8 carbon atoms, alkynyl
having 2 to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms,
cycloalkylalkyl having 4 to 10 carbon atoms, alkoxy having 1 to 8
carbon atoms, halogen, amino cyano, hydroxyl, nitro, halogenated
alkyl having 1 to 8 carbon atoms, halogenated alkoxy having 1 to 8
carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms,
hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8
carbon atoms, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, cycloalkylamino wherein the cycloalkyl portion has 3 to 7
carbon atoms, cycloalkylalkylamino wherein the cycloalkylalkyl
portion has 4 to 8 carbon atoms, carboxy, alkoxycarbonyl
alkylaminocarbonyl, acylamido, acyloxy, alkylthio having 1 to 8
carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms, sulfo sulfonylamino,
aryl containing 6 to 10 carbon atoms which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, heterocyclic group which is fully saturated, partially
saturated or fully unsaturated, having 5 to 10 ring atoms in which
at least 1 ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, or combinations thereof; and Het is a heterocyclic group
which is fully saturated, partially saturated or fully unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, O
or S atom, which is unsubstituted or substituted one or more times
by alkyl having 1 to 8 carbon atoms, alkenyl having 2 to 8 carbon
atoms, alkynyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 8
carbon atoms, cycloalkylalkyl having 4 to 10 carbon atoms, alkoxy
having 1 to 8 carbon atoms, halogen, amino, cyano, hydroxyl, nitro,
halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxy
having 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon
atoms, hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having
3 to 8 carbon atoms, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, cycloalkylamino wherein the cycloalkyl portion has 3 to 7
carbon atoms, cycloalkylalkylamino wherein the cycloalkylalkyl
portion has 4 to 8 C atoms, carboxy, alkoxycarbonyl
alkylaminocarbonyl, acylamido, acyloxy, alkylthio having 1 to 8
carbon atoms, alkylsulphinyl having 1 to 8 carbon atoms,
alkylsulphonyl having 1 to 8 carbon atoms, sulfo sulfonylamino,
aryl containing 6 to 10 carbon atoms which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, heterocyclic group which is fully saturated, partially
saturated or fully unsaturated, having 5 to 10 ring atoms in which
at least 1 ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, halogenated alkyl having 1 to 8 carbon atoms, alkoxy
having 1 to 4 carbon atoms, amino, monoalkylamino wherein the alkyl
portion has 1 to 8 carbon atoms, dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, cyano, hydroxy, nitro, oxo
or thio, or combinations thereof; or a pharmaceutically acceptable
salt thereof.
31. (canceled)
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
45. (canceled)
46. (canceled)
47. (canceled)
48. (canceled)
49. (canceled)
50. (canceled)
51. (canceled)
52. (canceled)
53. (canceled)
54. A compound according to claim 1, wherein X.sup.1 to X.sup.4 are
each, independently, CR.sup.1.
55. A compound according to claim 54, wherein: R.sup.1 is H,
CH.sub.3, C.sub.2H.sub.5, C.sub.2H.sub.3, or C.sub.3H.sub.5, which
in each case is unsubstituted or substituted one or more times by
F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof, C.sub.2H
or C.sub.3H.sub.3, which in each case is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.2,
NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4,
Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or combinations thereof,
OCH.sub.3, or OC.sub.2H.sub.5, which in each case is unsubstituted
or substituted one or more times by F, Cl, Br, I, CN, OR.sup.2,
NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations
thereof, Ar, Het, or F, Cl, Br, I, CN, NO.sub.2, NR.sup.3R.sup.4,
SR.sup.4, SOR.sup.4, SO.sub.2R.sup.4, SO.sub.2NR.sup.3R.sup.4,
NR.sup.3SO.sub.2R.sup.4, CONR.sup.3R.sup.4CSNR.sup.3R.sup.4,
COOR.sup.4, NR.sup.3COR.sup.4, NR.sup.3CSR.sup.4,
NR.sup.3CONR.sup.3R.sup.4NR.sup.3CSNR.sup.3R.sup.4,
NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4, OCONR.sup.3R.sup.4, or
OCSNR.sup.3R.sup.4; R.sup.2 is H, CH.sub.3, C.sub.2H.sub.5,
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, or
cyclopropylmethyl, which, in each case, is unsubstituted or
substituted one or more by F, Cl, Br, I, CN, OH, alkoxy having 1 to
4 carbon atoms, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar,
Het, or combinations thereof; R.sup.3 and R.sup.4 are each
independently H, CH.sub.3, C.sub.2H.sub.5, C.sub.2H.sub.3, or
C.sub.3H.sub.5, which, in each case, is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1
to 6 carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, C.sub.2H or
C.sub.3H.sub.3, which in each case is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon
atoms, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations thereof, cyclopropyl, cyclobutyl, or cyclopentyl,
which in each case is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, cyclopentylmethyl or
cyclopropylmethyl, which in each case is unsubstituted or
substituted in the cycloalkyl portion one or more times by F, Cl,
Br, I, CN, alkoxy having 1 to 6 carbon atoms, monoalkylamino having
1 to 6 carbon atoms, dialkylamino wherein each alkyl group has 1 to
6 carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6
carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, Ar, or Het;
Ar is phenyl, naphthyl or biphenyl, which in each case is
unsubstituted or substituted one or more times by halogen, alkyl
having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon
atoms, nitro, amino, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy
having 1 to 8 carbon atoms, carboxy, cyano, alkoxycarbonyl 2 to 9
carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl
having 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon
atoms, phenoxy, acetoxy, or combinations thereof; and Het is furyl,
thienyl, bithienyl, benzylprazolyl, thiazolyl, imidazolyl,
methylimidazolyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,
dihydropyranyl, or tetrahydropyranyl, which in each case is
unsubstituted or substituted one or more times by halogen, alkyl
having 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon
atoms, nitro, amino, monoalkylamino having 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy
having 1 to 8 carbon atoms, carboxy, cyano, alkoxycarbonyl 2 to 9
carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinyl
having 1 to 8 C carbon atoms, alkylsulphonyl having 1 to 8 carbon
atoms, phenoxy, acetoxy, or combinations thereof.
56. A compound according to claim 54, wherein X.sup.2 is CR.sup.1
wherein R.sup.1 is not H, and X.sup.1, X.sup.3 and X.sup.4 are each
CH; X.sup.3 is CR.sup.1 wherein R.sup.1 is not H, and X.sup.1,
X.sup.2, and X.sup.4 are each CH; X.sup.4 is CR.sup.1 wherein
R.sup.1 is not H, and X.sup.1, X.sup.2, and X.sup.3 are each
CH.
57. A compound according to claim 54, wherein R.sup.1 is H or
Het.
58. A compound according to claim 55, wherein: R.sup.1 is H,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3, C.sub.2H.sub.3, or
C.sub.3H.sub.5, C.sub.2H or C.sub.3H.sub.3, which in each case is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4,
Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or combinations thereof,
OCH.sub.3, OC.sub.2H.sub.5, OCF.sub.3, or OCHF.sub.2, Ar, Het, or
F, Cl, Br, I, CN, NO.sub.2, NR.sup.3R.sup.4, SR.sup.4, SOR.sup.4,
SO.sub.2R.sup.4, SO.sub.2NR.sup.3R.sup.4, NR.sup.3SO.sub.2R.sup.4,
CONR.sup.3R.sup.4, CSNR.sup.3R.sup.4, COOR.sup.4,
NR.sup.3COR.sup.4, NR.sup.3CSR.sup.4, NR.sup.3CONR.sup.3R.sup.4,
NR.sup.3CSNR.sup.3R.sup.4, NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4,
OCONR.sup.3R.sup.4, or OCSNR.sup.3R.sup.4; R.sup.2 is H, or
CH.sub.3, C.sub.2H.sub.5, CF.sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentylmethyl, or cyclopropylmethyl; and R.sup.3
and R.sup.4 are each independently H, CH.sub.3, C.sub.2H.sub.5,
CF.sub.3, C.sub.2H.sub.3, or C.sub.3H.sub.5, C.sub.2H or
C.sub.3H.sub.3, which in each case is unsubstituted or substituted
one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon
atoms, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations thereof, cyclopropyl, cyclobutyl, or cyclopentyl,
which in each case is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, cyclopentylmethyl or
cyclopropylmethyl, which in each case is unsubstituted or
substituted in the cycloalkyl portion one or more times by F, Cl,
Br, I, CN, alkoxy having 1 to 6 carbon atoms, monoalkylamino having
1 to 6 carbon atoms, dialkylamino wherein each alkyl group has 1 to
6 carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, and/or substituted in the alkyl portion one or more times
by one or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6
carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, Ar, or
Het.
59. A compound according to claim 58, wherein X is CR.sup.1 wherein
R.sup.1 is not H, and X.sup.1, X.sup.3, and X.sup.4 are each CH;
X.sup.3 is CR.sup.1 wherein R.sup.1 is not H, and X.sup.1, X.sup.2,
and X.sup.4 are each CH; X.sup.4 is CR.sup.1 wherein R.sup.1 is not
H, and X.sup.1, X.sup.2, and X.sup.3 are each CH.
60. A compound according to claim 58, wherein R.sup.1 is H or
Het.
61. A compound according to claim 1, wherein X.sup.1 is CH, at
least one of X.sup.2, X.sup.3, and X.sup.4 is CR.sup.1 wherein
R.sup.1 is not H.
Description
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/637,771, filed Dec. 22, 2004, the entire
disclosure of which is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
ligands for nicotinic acetylcholine receptors (nAChR), activation
of nAChRs, and the treatment of disease conditions associated with
defective or malfunctioning nicotinic acetylcholine receptors,
especially of the brain. Further, this invention relates to novel
compounds, which act as ligands for the .alpha.7 nAChR subtype,
methods of preparing such compounds, compositions comprising such
compounds, and methods of use thereof.
BACKGROUND OF THE INVENTION
[0003] There are two types of receptors for the neurotransmitter,
acetylcholine: muscarinic receptors and nicotinic receptors, based
on the selectivity of action of muscarine and nicotine,
respectively. Muscarinic receptors are G-protein coupled receptors.
Nicotinic receptors are members of the ligand-gated ion channel
family. When activated, the conductance of ions across the
nicotinic ion channels increases.
[0004] Nicotinic alpha-7 receptor protein forms a homo-pentameric
channel in vitro that is highly permeable to a variety of cations
(e.g., Ca.sup.++). Each nicotinic alpha-7 receptor has four
transmembrane domains, named M1, M2, M3, and M4. The M2 domain has
been suggested to form the wall lining the channel. Sequence
alignment shows that nicotinic alpha-7 is highly conserved during
evolution. The M2 domain that lines the channel is identical in
protein sequence from chicken to human. For discussions of the
alpha-7 receptor, see, e.g., Revah et al. (1991), Nature, 353,
846-849; Gatzi et al. (1992), Nature 359, 500-505; Fucile et al.
(2000), PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J.
Pharmacol. 366 (2-3), 301-308; and Gopalakrishnan et al. (1995),
Eur. J. Pharmacol. 290(3), 237-246.
[0005] The nicotinic alpha-7 receptor channel is expressed in
various brain regions and is believed to be involved in many
important biological processes in the central nervous system (CNS),
including learning and memory. Nicotinic alpha-7 receptors are
localized on both presynaptic and postsynaptic terminals and have
been suggested to be involved in modulating synaptic transmission.
It is therefore of interest to develop novel compounds, which act
as ligands for the .alpha.7 nAChR subtype, for the treatment of
disease conditions associated with defective or malfunctioning
nicotinic acetylcholine receptors.
SUMMARY OF THE INVENTION
[0006] This invention relates to novel compounds, which act as
ligands for the .alpha.7 nAChR subtype, methods of preparing such
compounds, compositions comprising such compounds, and methods of
use thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention includes compounds of Formula I:
##STR00001##
wherein [0008] X.sup.1 to X.sup.4 are each, independently, N or
CR.sup.1, wherein at most one of X.sup.1 to X.sup.4 is N; [0009] B
is --C(O)--O-- or --C(O)--NH--CH.sub.2--; [0010] Y is O, S, or NH;
[0011] R.sup.1 is H, [0012] C.sub.1-4-alkyl, or C.sub.2-4-alkenyl,
which, in each case is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof (e.g.,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3, C.sub.2H.sub.3, or
C.sub.3H.sub.5), [0013] C.sub.2-4-alkynyl which is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, OR.sup.2,
NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl,
SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4,
Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or combinations thereof (e.g.,
C.sub.2H, C.sub.3H.sub.3), [0014] C.sub.1-4-alkoxy which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar,
Het, or combinations thereof (e.g., OCH.sub.3, OC.sub.2H.sub.5,
OCF.sub.3, OCHF.sub.2), [0015] Ar, [0016] Het, [0017] halogen
(e.g., F, Cl, Br, I), [0018] CN, NO.sub.2, NR.sup.3R.sup.4,
SR.sup.4, SOR.sup.4, SO.sub.2R.sup.4, SO.sub.2NR.sup.3R.sup.4,
NR.sup.3SO.sub.2R.sup.4, CONR.sup.3R.sup.4, CSNR.sup.3R.sup.4,
COOR.sup.4, NR.sup.3COR.sup.4, NR.sup.3CSR.sup.4,
NR.sup.3CONR.sup.3R.sup.4, NR.sup.3CSNR.sup.3R.sup.4,
NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4, OCONR.sup.3R.sup.4, or
OCSNR.sup.3R.sup.4; [0019] R.sup.2 is H, [0020] C.sub.1-6-alkyl,
C.sub.3-8-cycloalkyl, or C.sub.4-8-cycloalkylalkyl, which, in each
case, is unsubstituted or substituted one or more by F, Cl, Br, I,
CN, OH, alkoxy having 1 to 4 carbon atoms, NR.sup.3R.sup.4, SH,
SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof (e.g.,
CH.sub.3, C.sub.2H.sub.5, CF.sub.3, cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentylmethyl, cyclopropylmethyl, etc.); [0021]
R.sup.3 and R.sup.4 are each independently [0022] H, [0023]
C.sub.1-6-alkyl or C.sub.3-6-alkenyl, which, in each case, is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl, Ar, Het,
or combinations thereof (e.g., CH.sub.3, C.sub.2H.sub.5, CF.sub.3,
C.sub.2H.sub.3, or C.sub.3H.sub.5), [0024] C.sub.3-6-alkynyl which
is unsubstituted or substituted one or more times by F, Cl, Br, I,
CN, alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl,
Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or combinations thereof (e.g.,
C.sub.2H, C.sub.3H.sub.3), [0025] C.sub.3-8-cycloalkyl which is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms (e.g., diethylamino), C.sub.3-8-cycloalkyl, Ar, Het,
or combinations thereof (e.g., cyclopropyl, cyclobutyl,
cyclopentyl), [0026] C.sub.4-10-cycloalkylalkyl which is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms (e.g., diethylamino),
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, and/or
substituted in the alkyl portion one or more times by one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms (e.g., diethylamino),
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof (e.g.,
cyclopentylmethyl, cyclopropylmethyl, etc.), [0027] Ar, or [0028]
Het; [0029] Ar is an aryl group containing 6 to 10 carbon atoms
which is unsubstituted or substituted one or more times by [0030]
alkyl having 1 to 8 carbon atoms, [0031] alkenyl having 2 to 8
carbon atoms, [0032] alkynyl having 2 to 8 carbon atoms, [0033]
cycloalkyl having 3 to 8 carbon atoms, [0034] cycloalkylalkyl
having 4 to 10 carbon atoms, [0035] alkoxy having 1 to 8 carbon
atoms, [0036] halogen (F, Cl, Br, or I, preferably F or Cl), [0037]
amino, [0038] cyano, [0039] hydroxyl, [0040] nitro, [0041]
halogenated alkyl having 1 to 8 carbon atoms, [0042] halogenated
alkoxy having 1 to 8 carbon atoms, [0043] hydroxyalkyl having 1 to
8 carbon atoms, [0044] hydroxyalkoxy having 2 to 8 carbon atoms,
[0045] alkenyloxy having 3 to 8 carbon atoms, [0046] monoalkylamino
having 1 to 8 carbon atoms, [0047] dialkylamino wherein the alkyl
portions each have 1 to 8 carbon atoms, [0048] cycloalkylamino
wherein the cycloalkyl portion has 3 to 7 carbon atoms, [0049]
cycloalkylalkylamino wherein the cycloalkylalkyl portion has 4 to 8
carbon atoms, [0050] carboxy, [0051] alkoxycarbonyl, [0052]
alkylaminocarbonyl, [0053] acylamido (e.g., acetamido), [0054]
acyloxy (e.g., acetoxy), [0055] alkylthio having 1 to 8 carbon
atoms, [0056] alkylsulphinyl having 1 to 8 carbon atoms, [0057]
alkylsulphonyl having 1 to 8 carbon atoms, [0058] sulfo, [0059]
sulfonylamino, [0060] aryl containing 6 to 10 carbon atoms (e.g.,
phenyl, naphthyl, biphenyl) which is unsubstituted or substituted
one or more times by halogen (F, Cl, Br, or I, preferably F or Cl),
alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8
carbon atoms, alkoxy having 1 to 4 carbon atoms, amino,
monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, cyano, hydroxy, nitro, oxo or thio, [0061] heterocyclic
group which is fully saturated, partially saturated or fully
unsaturated, having 5 to 10 ring atoms in which at least 1 ring
atom is a N, O or S atom, which is unsubstituted or substituted one
or more times by halogen (F, Cl, Br, or I, preferably F or Cl),
alkyl having 1 to 8 carbon atoms, halogenated alkyl having 1 to 8
carbon atoms, alkoxy having 1 to 4 carbon atoms, amino,
monoalkylamino wherein the alkyl portion has 1 to 8 carbon atoms,
dialkylamino wherein the alkyl portions each have 1 to 8 carbon
atoms, cyano, hydroxy, nitro, oxo or thio, or combinations thereof;
and [0062] Het is a heterocyclic group (e.g., furyl, thienyl,
methylthienyl, bithienyl, benzylprazolyl, thiazolyl,
methylthiazolyl, imidazolyl, methylimidazolyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl),
which is fully saturated, partially saturated or fully unsaturated,
having 5 to 10 ring atoms in which at least 1 ring atom is a N, O
or S atom, which is unsubstituted or substituted one or more times
by [0063] alkyl having 1 to 8 carbon atoms, [0064] alkenyl having 2
to 8 carbon atoms, [0065] alkynyl having 2 to 8 carbon atoms,
[0066] cycloalkyl having 3 to 8 carbon atoms, [0067]
cycloalkylalkyl having 4 to 10 carbon atoms, [0068] alkoxy having 1
to 8 carbon atoms, [0069] halogen (F, Cl, Br, or I, preferably F or
Cl), [0070] amino, [0071] cyano, [0072] hydroxyl, [0073] nitro,
[0074] halogenated alkyl having 1 to 8 carbon atoms, [0075]
halogenated alkoxy having 1 to 8 carbon atoms, [0076] hydroxyalkyl
having 1 to 8 carbon atoms, [0077] hydroxyalkoxy having 2 to 8
carbon atoms, [0078] alkenyloxy having 3 to 8 carbon atoms, [0079]
monoalkylamino having 1 to 8 carbon atoms, [0080] dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms, [0081]
cycloalkylamino wherein the cycloalkyl portion has 3 to 7 carbon
atoms, [0082] cycloalkylalkylamino wherein the cycloalkylalkyl
portion has 4 to 8 carbon atoms, [0083] carboxy, [0084]
alkoxycarbonyl, [0085] alkylaminocarbonyl, [0086] acylamido (e.g.,
acetamido), [0087] acyloxy (e.g., acetoxy), [0088] alkylthio having
1 to 8 carbon atoms, [0089] alkylsulphinyl having 1 to 8 carbon
atoms, [0090] alkylsulphonyl having 1 to 8 carbon atoms, [0091]
sulfo, [0092] sulfonylamino, [0093] aryl containing 6 to 10 carbon
atoms (e.g., phenyl, naphthyl, biphenyl) which is unsubstituted or
substituted one or more times by halogen (F, Cl, Br, or I,
preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated
alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon
atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8
carbon atoms, dialkylamino wherein the alkyl portions each have 1
to 8 carbon atoms, cyano, hydroxy, nitro, oxo or thio, [0094]
heterocyclic group which is fully saturated, partially saturated or
fully unsaturated, having 5 to 10 ring atoms in which at least 1
ring atom is a N, O or S atom, which is unsubstituted or
substituted one or more times by halogen (F, Cl, Br, or I,
preferably F or Cl), alkyl having 1 to 8 carbon atoms, halogenated
alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 4 carbon
atoms, amino, monoalkylamino wherein the alkyl portion has 1 to 8
carbon atoms, dialkylamino wherein the alkyl portions each have 1
to 8 carbon atoms, cyano, hydroxy, nitro, oxo or thio, [0095] or
combinations thereof;
[0096] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) thereof, or solvates of pharmaceutically acceptable salts
thereof.
[0097] According to a further aspect of the invention, the
compounds of Formula I are selected from Formulas IA and IB:
##STR00002##
[0098] In accordance with a further aspect of the invention, the
compounds are selected from Formulas I, IA and IB wherein [0099]
R.sup.1 is H, [0100] CH.sub.3, C.sub.2H.sub.5, CF.sub.3,
C.sub.2H.sub.3, or C.sub.3H.sub.5, which in each case is
unsubstituted or substituted one or more times by F, Cl, Br, I, CN,
OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3, SOR.sup.3,
C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3, SO.sub.2NR.sup.3R.sup.4, Ar,
Het, or combinations thereof, [0101] C.sub.2H or C.sub.3H.sub.3,
which in each case is unsubstituted or substituted one or more
times by F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations thereof, [0102] OCH.sub.3, OC.sub.2Hs, OCF.sub.3, or
OCHF.sub.2, which in each case is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, OR.sup.2, NR.sup.3R.sup.4, SH,
SR.sup.3, SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof, [0103]
Ar, [0104] Het, [0105] F, Cl, Br, I, CN, NO.sub.2, NR.sup.3R.sup.4,
SR.sup.4, SOR.sup.4, SO.sub.2R.sup.4, SO.sub.2NR.sup.3R.sup.4,
NR.sup.3SO.sub.2R.sup.4, CONR.sup.3R.sup.4, CSNR.sup.3R.sup.4,
COOR.sup.4, NR.sup.3COR.sup.4, NR.sup.3CSR.sup.4,
NR.sup.3CONR.sup.3R.sup.4, NR.sup.3CSNR.sup.3R.sup.4,
NR.sup.3COOR.sup.4, NR.sup.3CSOR.sup.4, OCONR.sup.3R.sup.4, or
OCSNR.sup.3R.sup.4; [0106] R.sup.2 is H, [0107] CH.sub.3,
C.sub.2H.sub.5, CF.sub.3, cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentylmethyl, or cyclopropylmethyl, which, in each case, is
unsubstituted or substituted one or more by F, Cl, Br, I, CN, OH,
alkoxy having 1 to 4 carbon atoms, NR.sup.3R.sup.4, SH, SR.sup.3,
SOR.sup.3, C.sub.3-8-cycloalkyl, SO.sub.2R.sup.3,
SO.sub.2NR.sup.3R.sup.4, Ar, Het, or combinations thereof; [0108]
R.sup.3 and R.sup.4 are each independently [0109] H, [0110]
CH.sub.3, C.sub.2H.sub.5, CF.sub.3, C.sub.2H.sub.3, or
C.sub.3H.sub.5, which, in each case, is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1
to 6 carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, [0111]
C.sub.2H or C.sub.3H.sub.3, which in each case is unsubstituted or
substituted one or more times by F, Cl, Br, I, CN, alkoxy having 1
to 6 carbon atoms, monoalkylamino having 1 to 6 carbon atoms,
dialkylamino wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Si(C.sub.1-6-alkyl).sub.3, Ar, Het, or
combinations thereof, [0112] cyclopropyl, cyclobutyl, or
cyclopentyl, which in each case is unsubstituted or substituted one
or more times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon
atoms, monoalkylamino having 1 to 6 carbon atoms, dialkylamino
wherein each alkyl group has 1 to 6 carbon atoms,
C.sub.3-8-cycloalkyl, Ar, Het, or combinations thereof, [0113]
cyclopentylmethyl or cyclopropylmethyl, which in each case is
unsubstituted or substituted in the cycloalkyl portion one or more
times by F, Cl, Br, I, CN, alkoxy having 1 to 6 carbon atoms,
monoalkylamino having 1 to 6 carbon atoms, dialkylamino wherein
each alkyl group has 1 to 6 carbon atoms, C.sub.3-8-cycloalkyl, Ar,
Het, or combinations thereof, and/or substituted in the alkyl
portion one or more times by one or more times by F, Cl, Br, I, CN,
alkoxy having 1 to 6 carbon atoms, monoalkylamino having 1 to 6
carbon atoms, dialkylamino wherein each alkyl group has 1 to 6
carbon atoms, C.sub.3-8-cycloalkyl, Ar, Het, or combinations
thereof, [0114] Ar, or [0115] Het; [0116] Ar is phenyl, napthyl or
biphenyl, which in each case is unsubstituted or substituted one or
more times by halogen, alkyl having 1 to 8 carbon atoms, hydroxy,
alkoxy having 1 to 8 carbon atoms, nitro, amino, monoalkylamino
having 1 to 8 carbon atoms, dialkylamino wherein the alkyl portions
each have 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon
atoms, hydroxyalkoxy having 1 to 8 carbon atoms, carboxy, cyano,
alkoxycarbonyl 2 to 9 carbon atoms, alkylthio having 1 to 8 carbon
atoms, alkylsulphinyl having 1 to 8 carbon atoms, alkylsulphonyl
having 1 to 8 carbon atoms, phenoxy, acetoxy, or combinations
thereof, and [0117] Het is furyl, thienyl, bithienyl,
benzylprazolyl, thiazolyl, imidazolyl, methylimidazolyl,
pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydropyranyl, or
tetrahydropyranyl, which in each case is unsubstituted or
substituted one or more times by halogen, alkyl having 1 to 8
carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, nitro,
amino, monoalkylamino having 1 to 8 carbon atoms, dialkylamino
wherein the alkyl portions each have 1 to 8 carbon atoms,
hydroxyalkyl having 1 to 8 carbon atoms, hydroxyalkoxy having 1 to
8 carbon atoms, carboxy, cyano, alkoxycarbonyl 2 to 9 carbon atoms,
alkylthio having 1 to 8 carbon atoms, alkylsulphinyl having 1 to 8
C carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms, phenoxy,
acetoxy, or combinations thereof;
[0118] and pharmaceutically acceptable salts or solvates (e.g.,
hydrates) thereof, or solvates of pharmaceutically acceptable salts
thereof.
[0119] Alkyl throughout means a straight-chain or branched-chain
aliphatic hydrocarbon radical having preferably 1 to 4 carbon
atoms, unless otherwise indicated. Suitable alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
The alkyl group can also be substituted.
[0120] Alkenyl throughout means a straight-chain or branched-chain
alkyl radical having preferably 2 to 6 carbon atoms, especially 2
to 4 carbon atoms, unless otherwise indicated, wherein at least one
CH.sub.2CH.sub.2 group is replaced by CH.dbd.CH. Suitable alkenyl
groups include ethenyl, propenyl, butenyl, etc. The alkenyl group
can also be substituted.
[0121] Alkynyl throughout means a straight-chain or branched-chain
alkyl radical having preferably 2 to 6 carbon atoms, especially 2
to 4 carbon atoms, unless otherwise indicated, wherein at least one
CH.sub.2CH.sub.2 group is replaced by C.ident.C. Suitable alkynyl
groups include ethynyl, propynyl, butynyl, etc. The alkynyl group
can also be substituted.
[0122] Alkoxy means alkyl-O-- groups in which the alkyl portion
preferably has 1 to 4 carbon atoms, unless otherwise indicated.
Suitable alkoxy groups include methoxy, ethoxy, propoxy,
isopropoxy, isobutoxy, and sec-butoxy.
[0123] Cycloalkyl means a cyclic, bicyclic or tricyclic saturated
hydrocarbon radical having 3 to 8 carbon atoms, unless otherwise
indicated. Suitable cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl. Other suitable cycloalkyl
groups include spiropentyl, bicyclo[2.2.1]heptyl, and
bicyclo[2.2.2]octyl.
[0124] The cycloalkyl groups can be substituted by, for example, F,
Cl, Br, C.sub.1-4-alkyl, C.sub.1-4-alkoxy, hydroxyl, amino,
monoalkylamino having 1 to 4 carbon atoms, and/or dialkylamino in
which each alkyl group has 1 to 4 carbon atoms.
[0125] Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which
the cycloalkyl and alkyl portions are in accordance with previous
discussions. Suitable examples include cyclopropylmethyl and
cyclopentylmethyl.
[0126] Cycloalkyloxy refers to cycloalkyl-oxy radicals in which the
cycloalkyl portion is in accordance with previous discussions.
Suitable examples include cyclopropyloxy and cyclopentyloxy.
[0127] Ar, as a group or substituent per se or as part of a group
or substituent, refers to an aromatic carbocyclic radical
containing 6 to 10 carbon atoms, unless indicated otherwise.
Suitable aryl groups include phenyl, napthyl and biphenyl.
Substituted aryl groups include the above-described aryl groups
which are substituted one or more times by halogen, alkyl, hydroxy,
alkoxy, nitro, amino, alkylamino, dialkylamino, hydroxyalkyl,
hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,
alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g.,
acetoxy).
[0128] Het refers to saturated, partially saturated and fully
unsaturated heterocyclic groups having one, two or three rings and
a total number of 5 to 10 ring atoms wherein at least one of the
ring atoms is an N, O or S atom. Preferably, the heterocyclic group
contains 1 to 3 hetero-ring atoms selected from N, O and S.
Suitable saturated and partially saturated heterocyclic groups
include, but are not limited to tetrahydrofuranyl,
tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, isoxazolinyl and the like.
Suitable heteroaryl groups include but are not limited to furyl,
thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl,
indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like.
Other examples of suitable heterocyclic groups, are 2-quinolinyl,
1,3-benzodioxoyl, 2-thienyl, 2-benzofuranyl, 2-benzothiophenyl,
3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl,
3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl,
2-pyrrolyl, 3,4-1,2-benzopyran-6-yl, 5-indolyl,
1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl, 5-benzofuranyl,
2-isoimidazol-4-yl, 3-pyrazolyl, 3-carbazolyl, 2-thiazolyl,
2-oxazolyl, and 2-imidazolyl.
[0129] Substituted heterocyclic groups refer to the heterocyclic
groups described above, which are substituted in one or more places
by, for example, halogen, aryl, alkyl, hydroxy, alkoxy, cyano,
trifluoromethyl, nitro, oxo, amino, alkylamino, and
dialkylamino.
[0130] Radicals which are substituted one or more times preferably
have 1 to 3 substituents, especially 1 or 2 substituents of the
exemplified substituents. Halogenated radicals such as halogenated
alkyls are preferably fluorinated and include perhalo radicals such
as trifluoromethyl.
[0131] In accordance with a further aspect of the invention,
X.sup.1 is preferably CH.
[0132] In accordance with a further aspect of the invention,
X.sup.2 is CH or CR.sup.1. For example, X.sup.2 is CH or CR.sup.1
wherein R.sup.1 is Het (for example, thiazolyl, substituted
thiazolyl such as alkyl substituted thiazolyl (e.g.,
methylthiazolyl), tetrahydropyranyl, or dihydropyranyl),
C.sub.1-4-alkoxy (for example, --OCH.sub.3), or substituted
C.sub.1-4-alkoxy (e.g., --OCF.sub.3 or OCHF.sub.2).
[0133] In accordance with a further aspect of the invention,
X.sup.3 is CH or CR.sup.1. For example, X.sup.3 is CH or CR.sup.1
wherein R.sup.1 is Het (for example, thiazolyl, substituted
thiazolyl such as alkyl substituted thiazolyl (e.g.,
methylthiazolyl), tetrahydropyranyl, or dihydropyranyl),
C.sub.1-4-alkoxy (for example, --OCH.sub.3), or substituted
C.sub.1-4-alkoxy (e.g., --OCF.sub.3 or OCHF.sub.2).
[0134] In accordance with a further aspect of the invention,
X.sup.4 is CH or CR.sup.1. For example, X.sup.4 is CH or CR.sup.1
wherein R.sup.1 is substituted or unsubstituted C.sub.1-4-alkoxy
(e.g., OCF.sub.3 or OCHF.sub.2). More preferably, X.sup.4 is
CH.
[0135] In accordance with another aspect of the invention, X.sup.1
to X.sup.4 are each CH or CR.sup.1 wherein R.sup.1 is not H.
According to a further aspect of the invention, X.sup.1 and X.sup.4
are each CH. According to a further aspect of the invention,
X.sup.2 is CR.sup.1 wherein R.sup.1 is not H, and X.sup.1, X.sup.3,
and X.sup.4 are each CH. According to a further aspect of the
invention, X.sup.3 is CR.sup.1 wherein R.sup.1 is not H, and
X.sup.1, X.sup.2, and X.sup.4 are each CH. In addition, according
to a further aspect of the invention, X.sup.4 is CR.sup.1 wherein
R.sup.1 is not H, and X.sup.1, X.sup.2, and X.sup.3 are each
CH.
[0136] In accordance with a further aspect of the invention,
preferred R.sup.1 groups include H and Het (for example, thiazolyl,
substituted thiazolyl such as alkyl substituted thiazolyl (e.g.,
methylthiazolyl), tetrahydropyranyl, or dihydropyranyl),
C.sub.1-4-alkoxy (for example, --OCH.sub.3), or substituted
C.sub.1-4-alkoxy (e.g., --OCF.sub.3 or OCHF.sub.2).
[0137] In accordance with a further aspect of the invention, Y is
preferably N or S, especially N.
[0138] According to a further compound and/or method aspect of the
invention, the compounds of Formula I are selected from: [0139]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0140]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate, [0141] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0142] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0143]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate, [0144] (3)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0145] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0146]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(difluoromethoxy)-1H-indazole-3-carboxylate hydroformate, [0147]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(difluoromethoxy)-1H-indazole-3-carboxylate, [0148]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate, [0149] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate, [0150]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate, [0151]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(trifluoromethoxy)-1H-indazole-3-carboxylate, [0152]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate hydroformate, [0153]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate, [0154]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate, [0155] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate, [0156]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate, [0157] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0158]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate, [0159] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0160] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0161]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate, [0162] (3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate, [0163]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate, [0164]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate, [0165]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1,2-benzisothiazole-3-carboxylate, [0166]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate hydroformate, [0167]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate, [0168]
N-1-(Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazole-3-ca-
rboxamide hydroformate, [0169]
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazole-3-ca-
rboxamide, [0170]
N-1-(Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide
hydroformate, and [0171]
N-1-(Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide-
;
[0172] wherein salts listed above can also be in the form of
another pharmaceutically acceptable salt, and free base forms
listed above can also be in the form of a pharmaceutically
acceptable salt,
[0173] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0174] wherein a compound listed above (in a free base form or
solvate thereof, or in the form of a pharmaceutically acceptable
salt or solvate thereof,) can also be in the form of a polymorph,
and
[0175] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0176] According to a further compound and/or method aspect of the
invention, the compounds of Formula I are selected from: [0177]
1-Azabicyclo[2.2.2]oct-3-yl 5-methoxy-1H-indazole-3-carboxylate
hydroformate, [0178] 1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate, [0179]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-ethoxy-1,2-benzisothiazole-3-carboxylate hydroformate, [0180]
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-ethoxy-1,2-benzisothiazole-3-carboxylate, [0181]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate hydroformate, [0182]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate, [0183]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate hydroformate, [0184]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate, [0185]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
7-methoxy-1H-indazole-3-carboxylate hydroformate, [0186]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
7-methoxy-1H-indazole-3-carboxylate, [0187]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(difluoromethoxy)-1H-indazole-3-carboxylate hydroformate, [0188]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(difluoromethoxy)-1H-indazole-3-carboxylate, [0189]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(trifluoromethoxy)-1H-indazole-3-carboxylate, [0190]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate, [0191]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate, [0192]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
7-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate, [0193]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
7-(trifluoromethoxy)-1H-indazole-3-carboxylate, [0194]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0195] (3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0196]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0197] (3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0198]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0199] (3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0200]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate, [0201] (3R)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate, [0202]
(3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate, and [0203] (3R)-1-Azabicyclo[2.2.2]oct-3-yl
5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate,
[0204] wherein salts listed above can also be in the form of
another pharmaceutically acceptable salt, and, free base forms
listed above can also be in the form of a pharmaceutically
acceptable salt,
[0205] wherein a compound listed above (in either a free base form
or in the form of a pharmaceutically acceptable salt) can also be
in the form of a solvate (such as a hydrate),
[0206] wherein a compound listed above (in a free base form or
solvate thereof, or in the form of a pharmaceutically acceptable
salt or solvate thereof,) can also be in the form of a polymorph,
and
[0207] wherein if the compound exhibits chirality it can be in the
form of a mixture of enantiomers such as a racemate or a mixture of
diastereomers, or can be in the form of a single enantiomer or a
single diastereomer.
[0208] Preferred aspects include pharmaceutical compositions
comprising a compound of this invention and a pharmaceutically
acceptable carrier and, optionally, another active agent as
discussed below; a method of stimulating or activating inhibiting
alpha-7 nicotinic receptors, e.g., as determined by a conventional
assay or one described herein, either in vitro or in vivo (in an
animal, e.g., in an animal model, or in a mammal or in a human); a
method of treating a neurological syndrome, e.g., loss of memory,
especially long-term memory, cognitive impairment or decline,
memory impairment, etc. method of treating a disease state
modulated by nicotinic alpha-7 activity, in a mammal, e.g., a
human, e.g., those mentioned herein.
[0209] The compounds of the present invention may be prepared
conventionally. Some of the known processes that can be used are
described below. All starting materials are known or can be
conventionally prepared from known starting materials.
[0210] The synthesis of similar compounds is disclosed in copending
U.S. application Ser. No. 10/669,645, filed Sep. 25, 2003, and Ser.
No. 11/089,544, filed Mar. 25, 2005, the entire disclosures of
which are hereby incorporated by reference.
[0211] Acids that can be used in the preparation of the bicyclobase
esters are commercially available, can be prepared by known
procedures described in the literature, or as described below. For
example, 7-trifluoromethoxyindazole-3-carboxylic acid is
commercially available. 5-Nitroindazole-3-acid can be prepared by
nitration of indazole-3-acid (Kamm, O.; Segur, J. B. Org. Syn.
Coll. Vol 1. 1941, 372). Bromoindazole acids and
5-trifluoromethoxyindazole-3-acid can be prepared from the
corresponding isatins by basic hydrolysis, diazotization, and
reduction (Snyder, H. R.; et al. J. Am. Chem. Soc. 1952, 74, 2009).
3-Substituted benzisothiazolecarboxylic acids can be prepared from
the corresponding thiophenols by reaction with oxalyl chloride and
aluminum chloride followed by treatment with hydroxylamine,
hydrogen peroxide, and sodium hydroxide. The thiazole substituted
indazole acids can be prepared from the bromoindazole acids by
esterification, palladium mediated cross-coupling with the
requisite thiazole zinc reagent (Reeder, M. R.; et. al. Org. Proc.
Res. Devel. 2003, 7, 696), and saponification. The oxazole
substituted indazole acids were prepared in a similar manner. The
dihydropyran and tetrahydropyran substituted indazole acids can be
prepared from the bromo acids by esterification, metal-halogen
exchange and trapping with tetrahydropyran-4-one, followed by
acid-mediated dehydration or reduction under acidic conditions.
Some substituted indazole-3-acids were prepared from simple benzene
derivatives. For example, 5-difluoromethoxyindazole-3-acid was
prepared from 3-bromo-4-nitrophenol by reaction with ethyl
difluoroacetate, reaction with diethyl malonate, decarboxylative
saponification, esterification, reduction of the nitro group, and
diazotization. 6-Difluoromethoxyindazole-3-acid was prepared in a
similar manner from 2-bromo-5-difluoromethoxynitrobenzene. The
2-bromo-5-difluoromethoxynitrobenzene used in that preparation was
prepared from 4-nitrophenol by ether formation, nitro reduction
with concomitant protection as the amide, nitration, amide
hydrolysis, and a Sandmeyer reaction with copper (I) bromide. The
bicycloamine used to prepare the amide derivatives was readily
prepared from quinuclidinone by reaction with tosylmethylisocyanide
followed by reduction.
[0212] The bicyclobase esters can be prepared by the coupling
reaction of acids with the bicycloalcohol using triphenylphosphine
and diisopropyl azodicarboxylate. (Ahn, C.; Correia, R.; DeShong,
P. J. Org. Chem., 2002, 67, 1751). Alternatively, the bicyclobase
esters can be prepared by the reaction of the acids with the
bicycloalcohol in the presence of either p-toluenesulfonyl chloride
or oxalyl chloride in pyridine. (Brewster, J. H.; Ciotti Jr., C. J.
J. Am. Chem. Soc., 1955, 77, 6214). The bicyclobase amides can be
prepared by the coupling reaction of acids with the bicycloamine
and HBTU, HATU, or HOBt and EDCI in DMF, or by converting the acids
to the corresponding acid chloride and then reaction with the
bicycloamine (Macor, J. E.; Gurley, D.; Lanthorn, T.; Loch, J.;
Mack, R. A.; Mullen, G.; Tran, O.; Wright, N.; Macor, J. E. Bioorg.
Med. Chem. Lett. 2001, 9, 319-321). The couplings are generally
performed at 0.degree. C. and maintained at room temperature for
18-24 hours. The resultant adducts can be isolated and purified by
standard techniques, such as chromatography or recrystallization,
practiced by those skilled in the art.
[0213] One of ordinary skill in the art will recognize that
compounds of Formulas I, IA, and IB can exist in different
tautomeric and geometrical isomeric forms. All of these compounds,
including cis isomers, trans isomers, diastereomic mixtures,
racemates, nonracemic mixtures of enantiomers, substantially pure,
and pure enantiomers, are within the scope of the present
invention. Substantially pure enantiomers contain no more than 5%
w/w of the corresponding opposite enantiomer, preferably no more
than 2%, most preferably no more than 1%.
[0214] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, for example,
by the formation of diastereoisomeric salts using an optically
active acid or base or formation of covalent diastereomers.
Examples of appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
Mixtures of diastereoisomers can be separated into their individual
diastereomers on the basis of their physical and/or chemical
differences by methods known to those skilled in the art, for
example, by chromatography or fractional crystallization. The
optically active bases or acids are then liberated from the
separated diastereomeric salts. A different process for separation
of optical isomers involves the use of chiral chromatography (e.g.,
chiral HPLC columns), with or without conventional derivation,
optimally chosen to maximize the separation of the enantiomers.
Suitable chiral HPLC columns are manufactured by Diacel, e.g.,
Chiracel OD and Chiracel OJ among many others, all routinely
selectable. Enzymatic separations, with or without derivitization,
are also useful. The optically active compounds of Formulas I, IA,
and IB can likewise be obtained by utilizing optically active
starting materials in chiral synthesis processes under reaction
conditions which do not cause racemization.
[0215] In addition, one of ordinary skill in the art will recognize
that the compounds can be used in different enriched isotopic
forms, e.g., enriched in the content of .sup.2H, .sup.3H, .sup.11C,
.sup.13C and/or .sup.14C. In one particular embodiment, the
compounds are deuterated. Such deuterated forms can be made the
procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As
described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration
can improve the efficacy and increase the duration of action of
drugs.
[0216] Deuterium substituted compounds can be synthesized using
various methods such as described in: Dean, Dennis C.; Editor.
Recent Advances in the Synthesis and Applications of Radiolabeled
Compounds for Drug Discovery and Development. [In: Curr., Pharm.
Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538
CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of
radiolabeled compounds via organometallic intermediates.
Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020.
CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony.
Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981),
64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN
1981:476229 CAPLUS.
[0217] Where applicable, the present invention also relates to
useful forms of the compounds as disclosed herein, such as base
free forms, and pharmaceutically acceptable salts or prodrugs of
all the compounds of the present invention for which salts or
prodrugs can be prepared. Pharmaceutically acceptable salts include
those obtained by reacting the main compound, functioning as a bas
with an inorganic or organic acid to form a salt, for example,
salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane
sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid,
succinic acid, citric acid, formic acid, hydrobromic acid, benzoic
acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid,
and carbonic acid. Pharmaceutically acceptable salts also include
those in which the main compound functions as an acid and is
reacted with an appropriate base to form, e.g., sodium, potassium,
calcium, magnesium, ammonium, and choline salts. Those skilled in
the art will further recognize that acid addition salts of the
claimed compounds may be prepared by reaction of the compounds with
the appropriate inorganic or organic acid via any of a number of
known methods. Alternatively, alkali and alkaline earth metal salts
can be prepared by reacting the compounds of the invention with the
appropriate base via a variety of known methods.
[0218] The following are further examples of acid salts that can be
obtained by reaction with inorganic or organic acids: acetates,
adipates, alginates, citrates, aspartates, benzoates,
benzenesulfonates, bisulfates, butyrates, camphorates,
digluconates, cyclopentanepropionates, dodecylsulfates,
ethanesulfonates, glucoheptanoates, glycerophosphates,
hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,
hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,
methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,
palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,
pivalates, propionates, succinates, tartrates, thiocyanates,
tosylates, mesylates and undecanoates.
[0219] For example, the pharmaceutically acceptable salt can be a
hydrochloride, a hydrobromide, a hydroformate, a maleate, or an
alkyllbenzenesulfonate salt (e.g., a C.sub.1-4-alkyll
benzenesulfonate salt such as 4-methylbenzenesulfonate salt).
[0220] Preferably, the salts formed are pharmaceutically acceptable
for administration to mammals. However, pharmaceutically
unacceptable salts of the compounds are suitable as intermediates,
for example, for isolating the compound as a salt and then
converting the salt back to the free base compound by treatment
with an alkaline reagent. The free base can then, if desired, be
converted to a pharmaceutically acceptable acid addition salt.
[0221] One of ordinary skill in the art will also recognize that
some of the compounds of Formulas I, IA, and IB can exist in
different polymorphic forms. As known in the art, polymorphism is
an ability of a compound to crystallize as more than one distinct
crystalline or "polymorphic" species. A polymorph is a solid
crystalline phase of a compound with at least two different
arrangements or polymorphic forms of that compound molecule in the
solid state. Polymorphic forms of any given compound are defined by
the same chemical formula or composition and are as distinct in
chemical structure as crystalline structures of two different
chemical compounds.
[0222] One of ordinary skill in the art will further recognize that
compounds of Formulas I, IA, and IB can exist in different solvate
forms. Solvates of the compounds of the invention may also form
when solvent molecules are incorporated into the crystalline
lattice structure of the compound molecule during the
crystallization process.
[0223] The compounds of the invention can be administered alone or
as an active ingredient of a formulation. Thus, the present
invention also includes pharmaceutical compositions of compounds of
Formulas I, IA, or IB, containing, for example, one or more
pharmaceutically acceptable carriers.
[0224] Numerous standard references are available that describe
procedures for preparing various formulations suitable for
administering the compounds according to the invention. Examples of
potential formulations and preparations are contained, for example,
in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (current edition); Pharmaceutical Dosage
Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current
edition, published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current
edition).
[0225] In view of their alpha-7 stimulating activity and,
preferably their high degree of selectivity, the compounds of the
present invention can be administered to anyone needing stimulation
of alpha-7 receptors. Administration may be accomplished according
to patient needs, for example, orally, nasally, parenterally
(subcutaneously, intravenously, intramuscularly, intrasternally and
by infusion) by inhalation, rectally, vaginally, topically and by
ocular administration.
[0226] Various solid oral dosage forms can be used for
administering compounds of the invention including such solid forms
as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk
powders. The compounds of the present invention can be administered
alone or combined with various pharmaceutically acceptable
carriers, diluents (such as sucrose, mannitol, lactose, starches)
and excipients known in the art, including but not limited to
suspending agents, solubilizers, buffering agents, binders,
disintegrants, preservatives, colorants, flavorants, lubricants and
the like. Time release capsules, tablets and gels are also
advantageous in administering the compounds of the present
invention.
[0227] Various liquid oral dosage forms can also be used for
administering compounds of the inventions, including aqueous and
non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
Such dosage forms can also contain suitable inert diluents known in
the art such as water and suitable excipients known in the art such
as preservatives, wetting agents, sweeteners, flavorants, as well
as agents for emulsifying and/or suspending the compounds of the
invention. The compounds of the present invention may be injected,
for example, intravenously, in the form of an isotonic sterile
solution. Other preparations are also possible.
[0228] Suppositories for rectal administration of the compounds of
the present invention can be prepared by mixing the compound with a
suitable excipient such as cocoa butter, salicylates and
polyethylene glycols. Formulations for vaginal administration can
be in the form of a pessary, tampon, cream, gel, past foam, or
spray formula containing, in addition to the active ingredient,
such suitable carriers as are known in the art.
[0229] For topical administration the pharmaceutical composition
can be in the form of creams, ointments, liniments, lotions,
emulsions, suspensions, gels, solutions, pastes, powders, sprays,
and drops suitable for administration to the skin, eye, ear or
nose. Topical administration may also involve transdermal
administration via means such as transdermal patches.
[0230] Aerosol formulations suitable for administering via
inhalation also can be made. For example, for treatment of
disorders of the respiratory tract, the compounds according to the
invention can be administered by inhalation in the form of a powder
(e.g., micronized) or in the form of atomized solutions or
suspensions. The aerosol formulation can be placed into a
pressurized acceptable propellant.
[0231] The compounds can be administered as the sole active agent
or in combination with other pharmaceutical agents such as other
agents used in the treatment of cognitive impairment and/or memory
loss, e.g., other .alpha.-7 agonists, PDE4 inhibitors, calcium
channel blockers, muscarinic m1 and m2 modulators, adenosine
receptor modulators, ampakines NMDA-R modulators, mGluR modulators,
dopamine modulators, serotonin modulators, cannabinoid modulators,
and cholinesterase inhibitors (e.g., donepezil, rivastigimin and
glanthanamine). In such combinations, each active ingredient can be
administered either in accordance with their usual dosage range or
a dose below their usual dosage range.
[0232] The compounds of the invention can be used in conjunction
with "positive modulators" which enhance the efficacy of nicotinic
receptor agonists. See, e.g., the positive modulators disclosed in
WO 99/56745, WO 01/32619, and WO 01/32622. Such combinational
therapy can be used in treating conditions/diseases associated with
reduced nicotinic transmission.
[0233] Further the compounds may be used in conjunction with
compounds that bind to A.beta. peptides and thereby inhibit the
binding of the peptides to .alpha.7nAChr subtypes. See, e.g., WO
99/62505.
[0234] The compounds of the present invention are nicotinic alpha-7
ligands, preferably agonists, especially partial agonists, for the
alpha-77 nicotinic acetylcholine receptor. Assays for determining
nicotinic acetylcholine activity are known within the art. See,
e.g., Davies, A. R., et al., Characterisation of the binding of
[3H]methyllycaconitine: a new radioligand for labelling alpha
7-type neuronal nicotinic acetylcholine receptors.
Neuropharmacology, 1999. 38(5): p. 679-90. As agonists for
.alpha.-7 nAChRs, the compounds are useful in the prophylaxis and
treatment of a variety of diseases and conditions associated with
the central nervous system. Nicotinic acetylcholine receptors are
ligand-gastrol ion-channel receptors that are composed of five
subunit proteins which form a central ion-conducting pore.
Presently, there are eleven known neuronal nAChR subunits
(.alpha.2-.alpha.9 and .beta.2-.beta.4). There are also five
further subunits expressed in the peripheral nervous system
(.alpha.1, .beta.1, .gamma., .delta., .epsilon.).
[0235] The nAChR receptor subtypes can be homopentameric or
heteropentameric. The subtype which has received considerable
attention is the homopentameric .alpha.7 receptor subtype formed
from five .alpha.7 subunits. The .alpha.7nAChRs exhibit a high
affinity for nicotine (agonist) and for .alpha.-bungarotoxin
(antagonist). Studies have shown the .alpha.7-nAChR agonists can be
useful in the treatment of psychotic diseases, neurodegenerative
diseases, and cognitive impairments, among other things. While
nicotine is a known agonist, there is a need for the development of
other .alpha.7-nAChR agonists, especially selective agonists, that
are less toxic or exhibit fewer side effects than nicotine.
[0236] The compound anabaseine, i.e.,
2-(3-pyridyl)-3,4,5,6-tetrahydropyridine is a naturally occurring
toxin in certain marine worms (nemertine worms) and ants. See,
e.g., Kem et al., Toxicon, 9:23, 1971. Anabaseine is a potent
activator of mammalian nicotinic receptors. Se e.g., Kem, Amer.
Zoologist, 25, 99, 1985. Certain anabaseine analogs such as
anabasine and DMAB
(3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2',3'-bipyridine)
are also known nicotinic receptor agonists. See, e.g., U.S. Pat.
No. 5,602,257 and WO 92/15306. One particular anabaseine analog,
(E-3-[2,4-dimethoxy-benzylidene]-anabaseine, also known as GTS-21
and DMXB (se e.g., U.S. Pat. No. 5,741,802), is a selective partial
.alpha.7-nAChR agonist that has been studied extensively. For
example, abnormal sensory inhibition is a sensory processing
deficit in schizophrenics and GTS-21 has been found to increase
sensory inhibition through interaction with .alpha.7-nAChRs. See,
e.g., Stevens et al., Psychopharmacology, 136: 320-27 (1998).
[0237] Another compound which is known to be a selective
.alpha.7-nAChR agonist is Tropisetron, i.e., 1H,
5.alpha.H-tropan-3.alpha.-yl indole-3-carboxylate. See J. E. Macor
et al., The 5-HT3-Antagonist Tropisetron (ICS 205-930) is a Potent
and Selective A7 Nicotinic Receptor Partial Agonist. Bioorg. Med.
Chem. Lett. 2001, 319-321).
[0238] The present invention further includes methods of treatment
that involve activation of .alpha.-7 nicotinic receptors. Thus, the
present invention includes methods of selectively
activating/stimulating .alpha.-7 nicotinic receptors in animals,
e.g., mammals, especially humans, wherein such
activation/stimulation has a therapeutic effect, such as where such
activation may relieve conditions involving neurological syndromes,
such as the loss of memory, especially long-term memory. Such
methods comprise administering to an animal in need thereof,
especially a mammal, most especially a human, an effective amount
of a compound of Formulas I, IA, or IB, alone or as part of a
formulation, as disclosed herein.
[0239] In accordance with a method aspect of the invention, there
is provided a method of treating a patient (e.g., a mammal such as
a human) suffering from a disease state (e.g., memory impairment)
comprising administering to the patient a compound according to
Formulas I, IA, or IB. Preferably, the disease state involves
decreased nicotinic acetylcholine receptor activity.
[0240] In accordance with a method aspect of the invention there is
provided a method for the treatment or prophylaxis of a disease or
condition resulting from dysfunction of nicotinic acetylcholine
receptor transmission in a mammal, e.g. a human, comprising
administering an effective amount of a compound according to
Formulas I, IA, or IB.
[0241] In accordance with a method aspect of the invention there is
provided a method for the treatment or prophylaxis of a disease or
condition resulting from defective or malfunctioning nicotinic
acetylcholine receptors, particularly .alpha.7nACh receptors, in a
mammal, e.g. a human, comprising administering an effective amount
of a compound according to Formulas I, IA, or IB.
[0242] In accordance with a method aspect of the invention there is
provided a method for the treatment or prophylaxis of a disease or
condition resulting from suppressed nicotinic acetylcholine
receptor transmission in a mammal, e.g., a human, comprising
administering an amount of a compound according to Formulas I, IA,
or IB effective to activate .alpha.7nACh receptors.
[0243] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
psychotic disorder, a cognition impairment (e.g., memory
impairment), or neurodegenerative disease in a mammal, e.g., a
human, comprising administering an effective amount of a compound
according to Formulas I, IA, or IB.
[0244] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
disease or condition resulting from loss of cholinergic synapses in
a mammal, e.g., a human, comprising administering an effective
amount of a compound according to Formulas I, IA, or IB.
[0245] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
neurodegenerative disorder by activation of .alpha.7nACh receptors
in a mammal, e.g., a human, comprising administering an effective
amount of a compound according to Formulas I, IA, or IB.
[0246] In accordance with another method aspect of the invention
there is provided a method for protecting neurons in a mammal,
e.g., a human, from neurotoxicity induced by activation of
.alpha.7nACh receptors comprising administering an effective amount
of a compound according to Formulas I, IA, or IB.
[0247] In accordance with another method aspect of the invention
there is provided a method for the treatment or prophylaxis of a
neurodegenerative disorder by inhibiting the binding of A.beta.
peptides to .alpha.7nACh receptors in a mammal, e.g., a human,
comprising administering an effective amount of a compound
according to Formulas I, IA, or IB.
[0248] In accordance with another method aspect of the invention
there is provided a method for protecting neurons in a mammal,
e.g., a human, from neurotoxicity induced by A.beta. peptides
comprising administering an effective amount of a compound
according to Formulas I, IA, or IB.
[0249] In accordance with another method aspect of the invention
there is provided a method for alleviating inhibition of
cholinergic function induced by A.beta. peptides in a mammal, e.g.,
a human, comprising administering an effective amount of a compound
according to Formulas I, IA, or IB.
[0250] Agents that bind to nicotinic acetylcholine receptors have
been indicated as useful in the treatment and/or prophylaxis of
various diseases and conditions, particularly psychotic diseases,
neurodegenerative diseases involving a dysfunction of the
cholinergic system, and conditions of memory and/or cognition
impairment, including, for example, schizophrenia, anxiety, mania,
depression, manic depression [examples of psychotic disorders],
Tourette's syndrome, Parkinson's disease, Huntington's disease
[examples of neurodegenerative diseases], cognitive disorders (such
as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral
Sclerosis, memory impairment, memory loss, cognition deficit,
attention deficit, Attention Deficit Hyperactivity Disorder), and
other uses such as treatment of nicotine addiction, inducing
smoking cessation, treating pain (i.e., analgesic use), providing
neuroprotection, treating jetlag, treating inflammation, and
treating sepsis. See, e.g., WO 97/30998; WO 99/03850; WO 00/42044;
WO 01/36417; Holladay et al., J. Med. Chem., 40:26, 4169-94 (1997);
Schmitt et al., Annual Reports Med. Chem., Chapter 5, 41-51 (2000);
Stevens et al., Psychopharmacology, (1998) 136: 320-27 (1998); and
Shytle et al., Molecular Psychiatry, (2002), 7, pp. 525-535.
[0251] Thus, in accordance with the invention, there is provided a
method of treating a patient, especially a human, suffering from
psychotic diseases, neurodegenerative diseases involving a
dysfunction of the cholinergic system, and conditions of memory
and/or cognition impairment, including, for example, schizophrenia,
anxiety, mania, depression, manic depression [examples of psychotic
disorders], Tourette's syndrome, Parkinson's disease, Huntington's
disease [examples of neurodegenerative diseases], and/or cognitive
disorders (such as Alzheimer's disease, Lewy Body Dementia,
Amyotrophic Lateral Sclerosis, memory impairment, memory loss,
cognition deficit, attention deficit, Attention Deficit
Hyperactivity Disorder) comprising administering to the patient an
effective amount of a compound according to Formulas I, IA, or
IB.
[0252] Neurodegenerative disorders included within the methods of
the present invention include, but are not limited to, treatment
and/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse
Lewy Body disease, progressive supranuclear palsy (Steel-Richardson
syndrome), multisystem degeneration (Shy-Drager syndrome), motor
neuron diseases including amyotrophic lateral sclerosis,
degenerative ataxias, cortical basal degeneration,
ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing
panencephalitis, Huntington's disease, Parkinson's disease,
synucleinopathies, primary progressive aphasia, striatonigral
degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,
olivopontocerebellar degenerations, Gilles De La Tourette's
disease, bulbar, pseudobulbar palsy, spinal muscular atrophy,
spinobulbar muscular atrophy (Kennedy's disease), primary lateral
sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease,
Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,
familial spastic disease, Wohlfart-Kugelberg-Welander disease,
spastic paraparesis, progressive multifocal leukoencephalopathy,
prion diseases (such as Creutzfeldt-Jakob,
Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial
insomnia), and neurodegenerative disorders resulting from cerebral
ischemia or infarction including embolic occlusion and thrombotic
occlusion as well as intracranial hemorrhage of any type
(including, but not limited to, epidural, subdural, subarachnoid
and intracerebral), and intracranial and intravertebral lesions
(including, but not limited to, contusion, penetration, shear,
compression and laceration).
[0253] In addition, .alpha.-7nAChRs agonists, such as the compounds
of the present invention can be used to treat age-related dementia
and other dementias and conditions with memory loss including
age-related memory loss, senility, vascular dementia, diffuse white
matter disease (Binswanger's disease), dementia of endocrine or
metabolic origin, dementia of head trauma and diffuse brain damage,
dementia pugilistica and frontal lobe dementia. See, e.g., WO
99/62505. Thus, in accordance with the invention, there is provided
a method of treating a patient, especially a human, suffering from
age-related dementia and other dementias and conditions with memory
loss comprising administering to the patient an effective amount of
a compound according to Formulas I, IA, or IB.
[0254] Thus, in accordance with a further embodiment, the present
invention includes methods of treating patients suffering from
memory impairment due to, for example, mild cognitive impairment
due to aging, Alzheimer's disease, schizophrenia, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob
disease, depression, aging, head trauma, stroke, CNS hypoxia,
cerebral senility, multiinfarct dementia and other neurological
conditions, as well as HIV and cardiovascular diseases, comprising
administering an effective amount of a compound according to
Formulas I, IA, or IB.
[0255] Amyloid precursor protein (APP) and A.beta. peptides derived
therefrom, e.g., A.beta..sub.1-40, A.beta..sub.1-42, and other
fragments, are known to be involved in the pathology of Alzheimer's
disease. The A.beta..sub.1-42 peptides are not only implicated in
neurotoxicity but also are known to inhibit cholinergic transmitter
function. Further, it has been determined that A.beta. peptides
bind to .alpha.-7 nAChRs. Thus, agents which block the binding of
the A.beta. peptides to .alpha.-7 nAChRs are useful for treating
neurodegenerative diseases. See, e.g., WO 99/62505. In addition,
stimulation .alpha.-7 nAChRs can protect neurons against
cytotoxicity associated with A.beta. peptides. See, e.g., Kihara,
T. et al., Ann. Neurol., 1997, 42, 159.
[0256] Thus, in accordance with an embodiment of the invention
there is provided a method of treating and/or preventing dementia
in an Alzheimer's patient which comprises administering to the
subject a therapeutically effective amount of a compound according
to Formulas I, IA, or IB to inhibit the binding of an amyloid beta
peptide (preferably, A.beta..sub.1-42) with nAChRs, preferable
.alpha.-7 nAChRs, most preferably, human .alpha.-7 nAChRs (as well
as a method for treating and/or preventing other clinical
manifestations of Alzheimer's disease that include, but are not
limited to, cognitive and language deficits, apraxias, depression,
delusions and other neuropsychiatric symptoms and signs, and
movement and gait abnormalities).
[0257] The present invention also provides methods for treating
other amyloidosis diseases, for example, hereditary cerebral
angiopathy, non neuropathic hereditary amyloid, Down's syndrome,
macroglobulinemia, secondary familial Mediterranean fever,
Muckle-Wells syndrome, multiple myeloma, pancreatic- and
cardiac-related amyloidosis, chronic hemodialysis anthropathy, and
Finnish and Iowa amyloidosis.
[0258] In addition, nicotinic receptors have been implicated as
playing a role in the body's response to alcohol ingestion. Thus,
agonists for .alpha.-7nAChR's can be used in the treatment of
alcohol withdrawal and in anti-intoxication therapy. Thus, in
accordance with an embodiment of the invention there is provided a
method of treating a patient for alcohol withdrawal or treating a
patient with anti-intoxication therapy comprising administering to
the patient an effective amount of a compound according to Formulas
I, IA, or IB.
[0259] Agonists for the .alpha.-7nAChR subtypes can also be used
for neuroprotection against damage associated with strokes and
ischemia and glutamate-induced excitotoxicity. Thus, in accordance
with an embodiment of the invention there is provided a method of
treating a patient to provide for neuroprotection against damage
associated with strokes and ischemia and glutamate-induced
excitotoxicity comprising administering to the patient an effective
amount of a compound according to Formulas I, IA, or IB.
[0260] As noted above, agonists for the .alpha.-7nAChR subtypes can
also be used in the treatment of nicotine addiction, inducing
smoking cessation, treating pain, and treating jetlag, obesity,
diabetes, inflammation, and sepsis. Thus, in accordance with an
embodiment of the invention there is provided a method of treating
a patient suffering from nicotine addiction, pain, jetlag, obesity
and/or diabetes, or a method of inducing smoking cessation in a
patient comprising administering to the patient an effective amount
of a compound according to Formulas I, IA, or IB.
[0261] The inflammatory reflex is an autonomic nervous system
response to an inflammatory signal. Upon sensing an inflammatory
stimulus, the autonomic nervous system responds through the vagus
nerve by releasing acetylcholine and activating nicotinic .alpha.7
receptors on macrophages. These macrophages in turn release
cytokines. Dysfunctions in this pathway have been linked to human
inflammatory diseases including rheumatoid arthritis, diabetes and
sepsis. Macrophages express the nicotinic .alpha.7 receptor and it
is likely this receptor that mediates the cholinergic
anti-inflamatory response. Therefore, compounds with affinity for
the .alpha.7nACh receptor on macrophages may be useful for human
inflammatory diseases including rheumatoid arthritis, diabetes and
sepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005,
257(2), 156-66.
[0262] Thus, in accordance with an embodiment of the invention
there is provided a method of treating a patient (e.g., a mammal,
such as a human) suffering from an inflammatory disease, such as,
but not limited to, rheumatoid arthritis, diabetes or sepsis,
comprising administering to the patient an effective amount of a
compound according to Formulas I, IA, or IB.
[0263] In addition, due to their affinity to .alpha.-7nAChR's,
labeled derivatives of the compounds of Formulas I, IA, or IB
(e.g., C.sup.11 or F.sup.18 labelled derivatives), can be used in
neuroimaging of the receptors within, e.g., the brain. Thus, using
such labeled agents in vivo imaging of the receptors can be
performed using, e.g., PET imaging.
[0264] The condition of memory impairment is manifested by
impairment of the ability to learn new information and/or the
inability to recall previously learned information. Memory
impairment is a primary symptom of dementia and can also be a
symptom associated with such diseases as Alzheimer's disease,
schizophrenia, Parkinson's disease, Huntington's disease, Pick's
disease, Creutzfeldt-Jakob disease, HIV, cardiovascular disease,
and head trauma as well as age-related cognitive decline.
[0265] Thus, in accordance with an embodiment of the invention
there is provided a method of treating a patient suffering from,
for example, mild cognitive impairment (MCI), vascular dementia
(VaD), age-associated cognitive decline (AACD), amnesia associated
w/open-heart-surgery, cardiac arrest, and/or general anesthesia,
memory deficits from early exposure of anesthetic agents, sleep
deprivation induced cognitive impairment, chronic fatigue syndrome,
narcolepsy, AIDS-related dementia, epilepsy-related cognitive
impairment, Down's syndrome, Alcoholism related dementia,
drug/substance induced memory impairments, Dementia Puglistica
(Boxer Syndrome), and animal dementia (e.g., dogs, cats, horses,
etc.) patient comprising administering to the patient an effective
amount of a compound according to Formulas I, IA, or IB.
[0266] The dosages of the compounds of the present invention depend
upon a variety of factors including the particular syndrome to be
treated, the severity of the symptoms, the route of administration,
the frequency of the dosage interval, the particular compound
utilized, the efficacy, toxicology profile, pharmacokinetic profile
of the compound, and the presence of any deleterious side-effects,
among other considerations.
[0267] The compounds of the invention can be administered to
mammals, particularly humans, at typical dosage levels customary
for .alpha.-7 nicotinic receptor agonists such as the known
.alpha.-7 nicotinic receptor agonist compounds mentioned above. For
example, the compounds can be administered, in single or multiple
doses, by oral administration at a dosage level of, for example,
0.0001-10 mg/kg/day, e.g., 0.01-10 mg/kg/day. Unit dosage forms can
contain, for example, 1-200 mg of active compound. For intravenous
administration, the compounds can be administered, in single or
multiple dosages.
[0268] In carrying out the procedures of the present invention it
is of course to be understood that reference to particular buffers,
media, reagents, cells, culture conditions and the like are not
intended to be limiting, but are to be read so as to include all
related materials that one of ordinary skill in the art would
recognize as being of interest or value in the particular context
in which that discussion is presented. For example, it is often
possible to substitute one buffer system or culture medium for
another and still achieve similar, if not identical, results. Those
of skill in the art will have sufficient knowledge of such systems
and methodologies so as to be able, without undue experimentation,
to make such substitutions as will optimally serve their purposes
in using the methods and procedures disclosed herein.
[0269] The present invention will now be further described by way
of the following non-limiting examples. In applying the disclosure
of these examples, it should be kept clearly in mind that other and
different embodiments of the methods disclosed according to the
present invention will no doubt suggest themselves to those of
skill in the relevant art.
[0270] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius; and,
unless otherwise indicated, all parts and percentages are by
weight.
[0271] The entire disclosures of all applications, patents and
publications, cited above and below, are hereby incorporated by
reference.
EXAMPLES
[0272] All spectra were recorded at 300 MHz on a Bruker Instruments
NMR unless otherwise stated. Coupling constants (J) are in Hertz
(Hz) and peaks are listed relative to TMS (.delta. 0.00 ppm).
Microwave reactions were performed using a Personal Chemistry
Optimizer.TM. microwave reactor in 2.5 mL or 5 mL Personal
Chemistry microwave reactor vials. All reactions were performed at
200.degree. C. for 600 s with the fixed hold time ON unless
otherwise stated. Sulfonic acid ion exchange resins (SCX) were
purchased from Varian Technologies. Analytical HPLC was performed
on 4.6 mm.times.100 mm Xterra RP.sub.18 3.5.mu. columns using a
gradient of 20/80 to 80/20 water (0.1% formic acid)/acetonitrile
(0.1% formic acid) over 6 min. Preparative HPLC was performed on 30
mm.times.100 mm Xtera Prep RP.sub.18 5.mu. columns using an 8 min
gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile
(0.1% formic acid).
Representative Procedures.
I. Acid Syntheses
Procedure 1
[0273] Procedure 1 provides a method for the conversion of
substituted isatins to the corresponding indazole-3-carboxylic
acids.
[0274] The conversion of the substituted isatins to the
corresponding indazole-3-carboxylic acids is essentially the same
method as described for indazole-3-carboxylic acid: Snyder, H. R.,
et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin
(22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was
heated at 50.degree. C. for 30 min. The burgundy solution was
allowed to cool to rt and was maintained for 1 h. The reaction
mixture was cooled to 0.degree. C. and was treated with a 0.degree.
C. solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This
solution was added through a pipet submerged below the surface of a
vigorously stirred solution of sulfuric acid (2.3 mL) in water (45
mL) at 0.degree. C. The addition took 15 min and the reaction was
maintained for an additional 30 min. A cold (0.degree. C.) solution
of tin (II) chloride dihydrate (52.7 mmol) in concentrated
hydrochloric acid (20 mL) was added to the reaction mixture over 10
min and the slurry was maintained for 60 min. The precipitated
solids were isolated by filtration, washed with water, and dried to
give a quantitative mass balance. The solid was recrystallized from
acetic acid (20 mL/g) to provide the acid as a light yellow solid.
The acids were coupled with 1,4-diazabicyclo[3.2.2]nonane according
to procedure A.
[0275] The following acids were prepared according to this method:
[0276] 5-Bromo-1H-indazole-3-carboxylic acid, [0277]
5-Methoxy-1H-indazole-3-carboxylic acid, [0278]
6-Methoxy-1H-indazole-3-carboxylic acid, [0279]
7-Methoxy-1H-indazole-3-carboxylic acid, [0280]
5-(Trifluoromethoxy)-1H-indazole-3-carboxylic acid, and [0281]
6-(Trifluoromethoxy)-1H-indazole-3-carboxylic acid.
Procedure 2
[0282] Procedure 2 provides a method for the preparation of
5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.
[0283] 3-Bromo-4-nitrophenol (10.0 mmol) was added to a suspension
of sodium hydroxide (29.0 mmol) in N,N-dimethylformamide (15 mL)
and the suspension was maintained for 15 min at rt. The reaction
mixture was cooled to 0.degree. C. and was treated with ethyl
chlorodifluoroacetate (20.0 mmol). The reaction mixture was heated
at 70.degree. C. for 16 h and was concentrated. The residue was
diluted with ice water (200 mL) and was extracted with ethyl
acetate (3.times.100 mL). The combined organic layers were dried
(magnesium sulfate) and concentrated to provide the difluoromethyl
ether in 75% yield as a yellow oil.
[0284] Diethyl malonate (328 mmol) was added dropwise to a
suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40
mL) at 0.degree. C. The reaction mixture was warmed to 60.degree.
C. and maintained for 0.5 h. A solution of the difluoromethyl ether
(149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the
reaction mixture was heated at 100.degree. C. for 5 h. The cooled
solution was poured onto ice water, and the aqueous layer was
extracted with dichloromethane (3.times.100 mL). The combined
organic layers were dried (magnesium sulfate) and concentrated to
give the crude diester in 112% yield as an oil. The diester (167
mmol), sodium hydroxide (500 mmol), and water (335 mL) were
combined and heated at 60.degree. C. for 1 h. The reaction mixture
was allowed to cool to rt and the aqueous layer was washed with
dichloromethane (3.times.100 mL). The pH of the aqueous layer was
cautiously adjusted to 1 with concentrated hydrochloric acid and
the reaction mixture was heated at 60.degree. C. for 1 h. The
suspension was cooled to 5.degree. C. and the solids were collected
by filtration and dried to provide the acid in 61% yield.
[0285] Acetyl chloride (203 mmol) was added dropwise to ethanol
(300 mL) at 0.degree. C. After 0.5 h, the acid (101 mmol) was added
and the reaction mixture was heated at reflux for 15 h. The
reaction mixture was concentrated and the residue was partitioned
between dichloromethane (200 mL) and saturated sodium bicarbonate
(100 mL). The aqueous layer was further extracted with
dichloromethane (2.times.200 mL) and the combined organic layers
were dried (magnesium sulfate) and concentrated to provide the
ester in 60% yield as a brown oil.
[0286] The ester (60.4 mmol) was dissolved in ethanol (103 mL),
diluted with water (71 mL), and was treated with ammonium chloride
(243 mmol) and iron powder (301 mmol). The reaction mixture was
heated at reflux for 10 minutes and the suspension was filtrated
through Celite and the filter cake was washed with ethanol three
times. The filtrate was concentrated, the residue was suspended in
2 N hydrochloric acid and was stirred vigorously for 0.5 h. The
aqueous layer was washed with ethyl acetate (3.times.50 mL) and the
pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer
was extracted with chloroform (3.times.100 mL) and the combined
organic layers were dried (magnesium sulfate). Acetic anhydride
(392 mmol), isoamyl nitrite (291 mmol), and potassium acetate (51.0
mmol) were added to the organic layer and the suspension was heated
at reflux for 16 h. The solution was evaporated and the residue was
partitioned between saturated sodium bicarbonate (50 mL) and
dichloromethane (100 mL). The aqueous layer was further extracted
with dichloromethane (2.times.100 mL) and the combined organic
layers were dried (magnesium sulfate) and concentrated to provide
the N-acetylindazole ester in 79% yield as a brown oil.
[0287] The ester (63.8 mmol), sodium hydroxide (193 mmol), and
water (65 mL) were combined and the reaction was maintained for 24
h at 60.degree. C. After cooling to rt, the aqueous layer was
washed with dichloromethane (3.times.50 mL). The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid. The
precipitated solids were collected by filtration, washed with water
and dichloromethane, and dried to provide the acid in 27%
yield.
[0288] The following acids were prepared according to this method:
[0289] 5-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
Procedure 3
[0290] Procedure 3 provides a method for the coupling between the
brominated carboxylic esters and zinc reagents to form alkyl- and
aryl-substituted derivatives.
[0291] A 5 mL microwave reaction vessel was charged with
bis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq)
and the bromo ester (0.30 mmol). The vessel was evacuated and
back-filled with argon gas. In a separate reaction vessel, solution
of the Grignard (1.2 mmol, 4 eq) was added to a 0.5 M solution of
zinc chloride (1.2 mmol, 4 eq) in tetrahydrofuran at rt. The
suspension was maintained for 30 min and the entire contents were
transferred to the reaction vessel via cannula. The vessel was
sealed and subjected to microwave irradiation at 100.degree. C. for
600 sec. The reaction was quenched with acetic acid (0.5 mL) and
concentrated. The residue was diluted with saturated sodium
bicarbonate and extracted with 9/1 dichloromethane/methanol
(5.times.40 L). The combined organic layers were dried (sodium
sulfate) and concentrated. The residue was purified by
chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide the
ester. The ester was added to a solution of 2 N sodium hydroxide
and the suspension was warmed to 60.degree. C. After 2 h the
solution was allowed to cool to room temperature and was acidified
to pH .about.2. The precipitated solids were collected by
filtration, washed with water, and dried to provide the acid as an
off-white to light yellow solid. The acid was coupled with
1,4-diazabicyclo[3.2.2]nonane according to procedure A.
[0292] The Grignard reagent of thiazole is commercially available.
Alternatively, the aryllithium and the corresponding arylzinc
reagent can be generated according to the procedure outlined by
Reeder, M. R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696. The
zinc reagents of oxazole, and related reagents were prepared
according to this procedure.
[0293] The following acids were prepared according to this method:
[0294] 5-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid, [0295]
6-(1,3-Thiazol-2-yl)-1H-indazole-3-carboxylic acid, [0296]
6-(1,3-Oxazol-2-yl)-1H-indazole-3-carboxylic acid, [0297]
5-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid, [0298]
5-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid, [0299]
6-(4-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid, and
[0300] 6-(5-Methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic
acid.
Procedure 4
[0301] Procedure 4 provides a preparation of substituted
benzisothiazole-3-carboxylic acids from the corresponding
thiophenols.
[0302] To a solution of 3-methoxythiophenol (26.7 mmol) in ether
(20 mL) was added oxalyl chloride (43 mmol) dropwise. The mixture
was heated at reflux for 1.5 h, cooled to rt, and concentrated in
vacuo. The resulting yellow oil was dissolved in dichloromethane
(50 mL), cooled to 0.degree. C., and was treated with aluminum
chloride (32.0 mmol) in portions. The mixture was heated at reflux
for 30 min, cooled to rt, and poured onto ice water with stirring.
The organic layer was separated and successively washed with
saturated, aqueous sodium bicarbonate, water, and brine. The
organic layer was dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by chromatography
(4/1 ethyl acetate/hexane) which provided
6-methoxy-1-benzothiophene-2,3-dione (47%) as an orange solid.
[0303] To a mixture of the dione (0.44 mmol) in 30% aqueous
solution of ammonium hydroxide (2.0 mL) was added 35% aqueous
solution hydrogen peroxide (0.2 mL) and the reaction mixture was
maintained for 12 h. The precipitated pink solids were isolated by
filtration, washed with water, and dried under high vacuum to
afford 6-methoxybenzisothiazole-3-carboxamide (42%).
[0304] To a solution of the amide (5.46 mmol) in methanol (100 mL)
was added 10 N sodium hydroxide (12 mL). The mixture was heated at
reflux for 12 h, cooled to rt, and was acidified to pH <2 by the
slow addition of conc. hydrochloric acid. The organic layer was
extracted with dichloromethane (2.times.) and was dried over sodium
sulfate. The crude product was purified by chromatography (300/50/1
dichloromethane/methanol/formic acid) to provide
6-methoxy-1,2-benzisothiazole-3-carboxylic acid (89%) as a pink
solid.
[0305] The following acids were prepared by this method: [0306]
6-Methoxy-1,2-benzisothiazole-3-carboxylic acid, and [0307]
6-Ethoxy-1,2-benzisothiazole-3-carboxylic acid.
Procedure 5
[0308] Procedure 5 provides a method for the trapping of indazole
aryllithiums with ketones and the coupling with 3-aminoquinuclidine
to form heterocyclic derivatives.
[0309] tert-Butyl 6-bromoindazole-3-carboxylate was prepared from
the acid by reaction with a 2-fold excess of
di-tert-butyldicarbonate followed by treatment with sodium
hydroxide. To a suspension of sodium hydride (60% mineral oil
dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at 0.degree. C.
was slowly added a solution of tert-butyl
6-bromoindazole-3-carboxylate (4.0 mmol) in tetrahydrofuran (4 mL).
After stirring for 0.5 h at 0.degree. C., the mixture was cooled to
-78.degree. C. and a 1.7 M solution of tert-butyllithium in pentane
(5.1 mmol) was added. After 0.5 h at -78.degree. C., a solution of
tetrahydropyran-4-one (5 mmol) in tetrahydrofuran (1 mL) was added
dropwise. The mixture was stirred at -78.degree. C. for 1 h and
warmed to 0.degree. C. The reaction mixture was quenched with
saturated aqueous ammonium chloride and the mixture was partitioned
between ethyl acetate (100 mL) and water (100 mL). The organic
layer was separated, washed with brine (50 mL), dried (magnesium
sulfate), and concentrated. The residue was purified by
chromatography (70/30 ethyl acetate/hexanes) to yield
6-(4-hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid
tert-butyl ester (68%) as a colorless solid.
[0310] 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic
acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic
acid (3 mL) and the mixture was maintained at room temperature for
16 h. The solvent was removed in vacuo and the residue was
triturated with ethyl acetate to provide
6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid
(76%).
[0311] 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic
acid tert-butyl ester (1.0 mmol) was dissolved in trifluoroacetic
acid (5 mL), triethylsilane (2 mL), and dichloromethane (3 mL) and
the mixture was refluxed for 16 h. The solvent was removed in vacuo
and the residue was triturated with ethyl acetate to provide
6-(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a
tan solid.
[0312] The following acids were prepared using this method: [0313]
5-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid, [0314]
6-(3,6-Dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid, [0315]
5-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid, and
[0316] 6-(Tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic
acid.
Procedure 6
[0317] Procedure 6 provides a method for the preparation of
6-difluoromethoxyindazole-3-acid from 4-nitrophenol.
[0318] 4-Nitrophenol (162 mmol) was added to a suspension of sodium
hydroxide (485 mmol) in N,N-dimethylformamide (150 mL) and the
suspension was maintained for 15 min at rt. The reaction mixture
was cooled to 0.degree. C. and was treated with ethyl
chlorodifluoroacetate (329 mmol). The reaction mixture was heated
at 70.degree. C. for 16 h and was concentrated. The residue was
diluted with ice water (200 mL) and was extracted with ethyl
acetate (3.times.100 mL). The combined organic layers were dried
(magnesium sulfate) and concentrated to provide the difluoromethyl
ether in 59% yield as a yellow oil.
[0319] The nitro ether (149 mmol) was dissolved in ethanol (37.5
mL), diluted with water (25 mL), and was treated with ammonium
chloride (84.7 mmol) and iron powder (105 mmol). The reaction
mixture was heated at reflux for 30 minutes and the suspension was
filtered through Celite. The filter cake was washed with ethanol
three times and the combined filtrates were concentrated. The
residue was dissolved in water and the pH adjusted to 9-10 with 5 M
sodium hydroxide. The aqueous layer was extracted with ethyl
acetate (3.times.100 mL) and the combined organic layers were dried
(magnesium sulfate) and concentrated to a yellow oil. The oil was
dissolved in acetic anhydride (23.5 mmol) and the reaction mixture
was maintained at rt for 16 h. The reaction mixture was diluted
with water (50 .mu.L) and was neutralized with solid sodium
bicarbonate. The precipitated solids were isolated by filtration,
washed with water, and dried to provide the acetamide in 62% yield
as a light yellow solid.
[0320] Acetic anhydride (19.6 mmol) was added to a solution of the
acetamide (13.2 mmol) in chloroform (20 mL) and the reaction
mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was
added dropwise and the reaction mixture was maintained at reflux
for 30 min. The cooled solution was diluted with water (20 mL) and
the aqueous layer was extracted with dichloromethane (3.times.10
mL). The combined organic layers were dried (magnesium sulfate) and
concentrated to provide the nitro-amide in 83% yield.
[0321] The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and
water (10 mL) were combined and the reaction mixture was maintained
for 1.5 hour at 60.degree. C. the reaction was allowed to cool to
rt and the precipitated solids were isolated by filtration, and
washed with water, and dried to provide the aniline in 98% yield as
a light yellow solid.
[0322] The aniline (15.7 mmol) was mixed with 40% hydrobromic acid
(14.3 g) and water (10 mL) and the reaction mixture was warmed to
80-90.degree. C. in order to completely dissolve the aniline. The
reaction mixture was cooled to 0.degree. C. and a solution of
sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15
min period. The solution was maintained for 40 minutes at
0-5.degree. C. and filtered. Copper (I) bromide (18.8 mmol) was
dissolved in 40% hydrobromic acid (21 mL) and was cooled to
0.degree. C. The solution of the diazo salt was added slowly to the
copper solution and the mixture was maintained for 30 min at
0-10.degree. C. The reaction mixture was heated at 60.degree. C.
for 30 min and then at 100.degree. C. for 10 min to ensure
completion. The reaction mixture was allowed to cool to rt and was
extracted with dichloromethane (3.times.40 mL). The combined
organic layers were washed with 1 M sodium hydroxide, water, 1 N
hydrochloric acid, and water. The organic layer was dried
(magnesium sulfate) and concentrated to provide the nitro bromide
in 76% yield as a light yellow solid.
[0323] Diethyl malonate (25.7 mmol) was added dropwise to a
suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5
mL) at 0.degree. C. The reaction mixture was warmed to 60.degree.
C. and maintained for 30 min. A solution of the nitro bromide (11.7
mmol) in dimethylsulfoxide (7 mL) was added dropwise and the
reaction mixture was heated at 100.degree. C. for 5 h. The cooled
solution was poured onto ice water and the aqueous layer was
extracted with dichloromethane (3.times.100 mL). The combined
organic layers were dried (magnesium sulfate) and concentrated to
give the crude diester as an oil. The diester (11.7 mmol), sodium
hydroxide (35 mmol), and water (20 mL) were combined and heated at
60.degree. C. for 1 h. The reaction mixture was allowed to cool to
rt and the aqueous layer was washed with dichloromethane
(3.times.100 mL). The pH of the aqueous layer was cautiously
adjusted to 1 with concentrated hydrochloric acid and the reaction
mixture was heated at 60.degree. C. for 1 h. The suspension was
cooled to 0.degree. C. and the solids were collected by filtration
and dried to provide the acid in 64% yield.
[0324] Acetyl chloride (15.3 mmol) was added dropwise to ethanol
(50 mL) at 0.degree. C. After 30 min, the acid (7.69 mmol) was
added and the reaction mixture was heated at reflux for 15 h. The
reaction mixture was concentrated and the residue was partitioned
between dichloromethane (20 mL) and saturated sodium bicarbonate
(10 mL). The aqueous layer was further extracted with
dichloromethane (2.times.20 mL) and the combined organic layers
were dried (magnesium sulfate) and concentrated to provide the
ester in 94% yield as a brown oil.
[0325] Acetic anhydride (6.0 mL) was added to a suspension of the
ester (3.64 mmol), and acetic acid (7.0 mL) at 0.degree. C. Zinc
dust (14.6 mmol) was added in portions over 15 min and the reaction
mixture was maintained for 30 min at 0.degree. C. and then for 1.5
h at rt. Additional zinc powder (6.15 mmol) was added and the
reaction maintained for 3 h. The suspension was filtered through
Celite and the filtrate was concentrated. The residue was
partitioned between saturated sodium bicarbonate (10 mL) and ethyl
acetate (20 mL). The aqueous layer was further extracted with ethyl
acetate (3.times.20 mL) and the combined organic layers were dried
(magnesium sulfate) and concentrated to provide the acetamide in
92% yield as a brown oil.
[0326] Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol),
and potassium acetate (2.04 mmol) were added to a solution of the
acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was
heated at reflux for 16 h. The solution was evaporated and the
residue was partitioned between saturated sodium bicarbonate (10
mL) and dichloromethane (20 mL). The aqueous layer was further
extracted with dichloromethane (2.times.20 mL) and the combined
organic layers were dried (magnesium sulfate) and concentrated to
provide the crude N-acetylindazole ester as a brown oil.
[0327] The ester (3.36 mmol), sodium hydroxide (10 mmol) and water
(5 mL) were combined and the reaction was maintained for 24 h at
60.degree. C. After cooling to rt, the aqueous layer was washed
with dichloromethane (3.times.30 mL). The aqueous layer was
adjusted to pH 1 with concentrated hydrochloric acid and the
precipitated solids were collected by filtration, washed with water
and dichloromethane, and dried to provide the acid in 26%
yield.
[0328] The following acid was prepared according to this method:
[0329] 6-(Difluoromethoxy)-1H-indazole-3-carboxylic acid.
II. Base Synthesis
Procedure 7
[0330] Procedure 6 details the preparation of
3-aminomethylquinuclidine from quinuclidinone.
[0331] A solution of tosylmethylisocyanide (50.0 mmol) in ethanol
(4 mL) was added to the solution of quinuclidone (40.0 mmol) in
ethylene glycol dimethyl ether (155 mL) and the mixture was cooled
to -5.degree. C. Solid potassium tert-butoxide (130 mmol) was added
in portions over 20 minutes. The reaction mixture was allowed to
warm to RT after 30 min and was maintained for an additional 3
hours. The reaction mixture was filtered and diluted with saturated
hydrochloric acid in isopropanol. Diethyl ether was added and the
solids were collected by filtration to provide the desired product
in 88% yield as a yellow solid.
[0332] Concentrated hydrochloric acid (12 mL) and 10% palladium on
carbon (9.6 g) were added to a solution of the nitrile (35.0 mmol)
in methanol (720 mL) at 0.degree. C. The reaction mixture was
maintained under an atmosphere of hydrogen gas for 4.5 hours. The
catalyst was removed by filtration through Celite and the filtrate
was concentrated to afford a yellow solid. This solid was dissolved
in methanol and re-precipitated with ethyl ether (400 mL). The
solids were collected by filtration and dried to provide the
desired product in 32% yield as a yellow solid. .sup.1H NMR
(CD.sub.3OD) .delta. 3.30 (m, 1H), 3.14 (m, 4H), 2.90 (m, 2H), 2.85
(m, 1H), 2.2 (m 1H), 2.0 (m, 1H), 1.85 (m, 2H), 1.6 (m, 1H).
III. Coupling and Derivatization Procedures
Representative Procedure A.
[0333] Procedure A provides a method for ester formation using
Mitsunobu conditions.
Example 1
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00003##
[0335] To a solution of
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylic acid (0.50
mmol), (3R)-quinuclidin-3-ol (0.57 mmol), and triphenylphosphine
(0.57 mmol) in tetrahydrofuran (5 mL) at 0.degree. C. was added a
solution of diisopropyl azodicarboxylate (0.57 mmol) in
tetrahydrofuran (1 mL). The mixture was allowed to warm to rt over
2 hours and was maintained for 16 h. The mixture was loaded on a
SCX column (5 g) and was washed with methanol. Product was eluted
with methanol/dimethylethylamine (9/1) and concentrated. The
residue was purified by preparative HPLC to produce the desired
product in 1% yield. .sup.1H NMR (CD.sub.3OD) .delta. 8.65 (s, 1H),
8.51 (s, 1H), 8.04 (d, J=6.0, 1H), 7.74 (d, J=6.0, 1H), 7.55 (s,
1H), 5.45 (m, 1H), 3.81 (m, 1H), 3.45-3.20 (m, 5H), 2.55 (s, 3H),
2.55 (m, 1H), 2.36 (m, 1H), 2.21-1.93 (m, 3H); LC/MS (EI) t.sub.R
4.7 min, m/z 369 (M.sup.++1).
Example 2
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate
##STR00004##
[0337] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 356 (M.sup.++1).
Example 3
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate hydroformate
##STR00005##
[0339] Prepared by Procedure A in 17% yield. LC/MS (EI) t.sub.R 2.4
min, m/z 302 (M.sup.++1).
Example 4
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate hydroformate
##STR00006##
[0341] Prepared by Procedure A in 20% yield. LC/MS (EI) t.sub.R 3.3
min, m/z 302 (M.sup.++1).
Example 5
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate
##STR00007##
[0343] Prepared by Procedure A in 14% yield. LC/MS (EI) t.sub.R 5.0
min, m/z 356 (M++1).
Example 6
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(difluoromethoxy)-1H-indazole-3-carboxylate hydroformate
##STR00008##
[0345] Prepared by Procedure A in 10% yield. LC/MS (EI) t.sub.R 4.3
min, m/z 338 (M++1).
Example 7
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00009##
[0347] Prepared by Procedure A in 10% yield. LC/MS (EI) t.sub.R 4.7
min, m/z 369 (M<++1).
Example 8
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00010##
[0349] Prepared by Procedure A in 1% yield. LC/MS (EI) t.sub.R 4.7
min, m/z 369 (M.sup.++1).
Example 9
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00011##
[0351] Prepared by Procedure A in 10% yield. LC/MS (EI) t.sub.R 2.8
min, m/z 356 (M++1).
Example 10
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00012##
[0353] Prepared by Procedure A in 7% yield. LC/MS (EI) t.sub.R 4.3
min, m/z 354 (M.sup.++1).
Example 11
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00013##
[0355] Prepared by Procedure A in 8% yield. LC/MS (EI) t.sub.R 3.0
min, m/z 356 (M.sup.++1).
Representative Procedure B.
[0356] Procedure B provides a method for ester formation using
tosyl chloride (or oxalyl chloride) activation.
Example 12
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate
##STR00014##
[0358] p-Toluenesulfonyl chloride (0.16 mmol) was added to a
0.degree. C. solution of
6-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.81 mmol) in
pyridine. (5.00 mL). (3S)-Quinuclidin-3-ol (0.81 mmol) was added
and the reaction mixture was allowed to warm to rt. The reaction
mixture was maintained for 16 h and was filtered and concentrated.
The residue was redissolved in methanol and loaded on a 5 g SCX
column. The column was washed with methanol and the product was
eluted with methanol/dimethylethylamine (9/1) and concentrated. The
residue was purified by preparative HPLC to produce the desired
product in 16% yield. Note: this procedure works equally well when
p-toluenesulfonyl chloride is replaced with oxalyl chloride.
.sup.1H NMR (CDCl.sub.3) .delta. 8.52 (s, 1H), 7.96 (d, J=8.9, 1H),
7.49 (s, 1H), 7.09 (d, J=8.9, 1H), 5.31 (m, 1H), 3.72-3.29 (m, 6H),
2.56 (m, 1H), 2.32 (m, 1H), 2.06-1.88 (m, 3H); LC/MS (EI) t.sub.R
4.9 min, m/z 356 (M.sup.++1).
Example 13
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(trifluoromethoxy)-1H-indazole-3-carboxylate
##STR00015##
[0360] Prepared by Procedure B in 3% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 356 (M.sup.++1).
Example 14
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate
##STR00016##
[0362] Prepared by Procedure B in 1% yield. LC/MS (EI) t.sub.R 2.5
min, m/z 302 (M.sup.++1).
Example 15
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate
##STR00017##
[0364] Prepared by Procedure B in 2% yield. LC/MS (EI) t.sub.R 2.5
min, m/z 302 (M.sup.++1).
Example 16
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
##STR00018##
[0366] Prepared by Procedure B in 3% yield. LC/MS (EI) t.sub.R 3.9
min, m/z 355 (M++1).
Example 17
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate
##STR00019##
[0368] Prepared by Procedure B in 4% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 369 (M.sup.++1).
Example 18
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate
##STR00020##
[0370] Prepared by Procedure B in 4% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 369 (M.sup.++1).
Example 19
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate
##STR00021##
[0372] Prepared by Procedure B in 2% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 369 (M.sup.++1).
Example 20
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
4-methylbenzenesulfonate
##STR00022##
[0374] Prepared by Procedure B in 0.3% yield. LC/MS (EI) t.sub.R
4.8 min, m/z 369 (M.sup.++1).
Example 21
(3S)-1-Azabicyclo[2.2.2]oct-3-yl
6-methoxy-1,2-benzisothiazole-3-carboxylate
##STR00023##
[0376] Prepared by Procedure B in 24% yield. LC/MS (EI) t.sub.R 4.3
min, m/z 319 (M.sup.++1).
Example 22
1-azabicyclo[2.2.2]oct-3-yl 5-methoxy-1H-indazole-3-carboxylate
hydroformate
##STR00024##
[0378] Prepared by Procedure B in 8% yield. LC/MS (EI) t.sub.R 2.9
min, m/z 302 (M.sup.++1).
Example 23
(3S)-1-azabicyclo[2.2.2]oct-3-yl
6-ethoxy-1,2-benzisothiazole-3-carboxylate hydroformate
##STR00025##
[0380] Prepared by Procedure B in 38% yield. LC/MS (EI) t.sub.R 4.7
min, m/z 333 (M.sup.++1).
Example 24
(3R)-1-azabicyclo[2.2.2]oct-3-yl
5-methoxy-1H-indazole-3-carboxylate hydroformate
##STR00026##
[0382] Prepared by Procedure B in 11% yield. LC/MS (EI) t.sub.R 2.5
min. m/z 302 (M.sup.++1).
Example 25
((3R)-1-azabicyclo[2.2.2]oct-3-yl
6-methoxy-1H-indazole-3-carboxylate hydroformate
##STR00027##
[0384] Prepared by Procedure B in 2% yield. LC/MS (EI) t.sub.R 3.3
min, m/z 302 (M.sup.++1).
Example 26
((3R)-1-azabicyclo[2.2.2]oct-3-yl
7-methoxy-1H-indazole-3-carboxylate hydroformate
##STR00028##
[0386] Prepared by Procedure B in 9% yield. LC/MS (EI) t.sub.R 2.9
min, m/z 302 (M.sup.++1).
Example 27
(3R)-1-azabicyclo[2.2.2]oct-3-yl
6-(difluoromethoxy)-1H-indazole-3-carboxylate hydroformate
##STR00029##
[0388] Prepared by Procedure B in 3% yield. LC/MS (EI) t.sub.R 4.7
min, m/z 338 (M.sup.++1).
Example 28
(3R)-1-azabicyclo[2.2.2]oct-3-yl.
5-(trifluoromethoxy)-1H-indazole-3-carboxylate
##STR00030##
[0390] Prepared by Procedure B in 3% yield. LC/MS (EI) t.sub.R 4.9
min, m/z 356 (M.sup.++1).
Example 29
((3R)-1-azabicyclo[2.2.2]oct-3-yl
6-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate
##STR00031##
[0392] Prepared by Procedure B in 12% yield. LC/MS (EI) t.sub.R 4.9
min, m/z 356 (M.sup.++1).
Example 30
(3R)-1-azabicyclo[2.2.2]oct-3-yl
7-(trifluoromethoxy)-1H-indazole-3-carboxylate hydroformate
##STR00032##
[0394] Prepared by Procedure B in 3% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 356 (M.sup.++1).
Example 31
(3R)-1-azabicyclo[2.2.2]oct-3-yl
5-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00033##
[0396] Prepared by Procedure B in 2% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 369 (M++1).
Example 32
(3R)-1-azabicyclo[2.2.2]oct-3-yl
5-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00034##
[0398] Prepared by Procedure B in 2% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 369 (M.sup.++1).
Example 33
(3R)-1-azabicyclo[2.2.2]oct-3-yl
6-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00035##
[0400] Prepared by Procedure B in 1% yield. LC/MS (EI) t.sub.R 4.8
min, m/z 369 (M.sup.++1).
Example 34
(3R)-1-azabicyclo[2.2.2]oct-3-yl
6-(5-methyl-1,3-thiazol-2-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00036##
[0402] Prepared by Procedure B in 1% yield. LC/MS (EI) t.sub.R 4.9
min, m/z 369 (M.sup.++1).
Example 35
(3R)-1-azabicyclo[2.2.2]oct-3-yl
5-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylate
hydroformate
##STR00037##
[0404] Prepared by Procedure B in 2% yield. LC/MS (EI) t.sub.R 3.9
min, m/z 354 (M.sup.++1).
Representative Procedure C.
[0405] Procedure C provides a method for amide formation using HATU
activation.
Example 36
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-5-trifluoromethoxy-1H-indazole-3-car-
boxamide hydroformate
##STR00038##
[0407] To a solution of
5-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.40 mmol) in
tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL) was
added 1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride
(0.40 mmol) and HATU (0.40 mmol). N,N-Diisopropylethylamine (10.0
mmol) was added and the reaction mixture was maintained for 16 h.
The reaction mixture was heated at 60.degree. C. for 1 h, and was
filtered and concentrated. The residue was redissolved in methanol
and loaded on a 5 g SCX column. The column was washed with methanol
and the product was eluted with methanol/dimethylethylamine (9/1)
and concentrated. The residue was purified by preparative HPLC to
produce the desired product in 20% yield. .sup.1H NMR (CDCl.sub.3)
.delta. 8.47 (s, 1H), 8.10 (s, 1H), 7.67 (d, J=9.1, 1H), 7.36 (d,
J=9.1, 1H), 3.63-3.52 (m, 3H), 3.48-3.23 (m, 4H), 3.08-3.01 (m,
1H), 2.66-2.44 (m, 1H), 2.32-2.22 (m, 1H), 2.14-2.08 (m, 1H),
2.06-1.85 (m, 3H); LC/MS (EI) t.sub.R 4.8 min, m/z 369
(M.sup.++1).
Example 37
N-(1-Azabicyclo[2.2.2]oct-3-ylmethyl)-6-methoxy-1H-indazole-3-carboxamide
hydroformate
##STR00039##
[0409] Prepared by Procedure C in 20% yield. LC/MS (EI) t.sub.R 2.5
min, m/z 315 (M.sup.++1).
Example 3
[3H]MLA Binding
Materials:
TABLE-US-00001 [0410] Rat Brain: Pel-Freez Biologicals, CAT No.
56004-2 Protease inhibitor cocktail tablet: Roche, CAT No.
1697498
Membrane Preparation:
[0411] Rat brains in 20 vol (w/v) of ice-cold 0.32 M sucrose with
protease inhibitors (one tablet per 50 ml,) were homogenized with a
polytron for 10 sec at setting 11, then centrifuged 10 min at 1000
g, 4.degree. C. The supernatant was centrifuged again for 20 min at
20,000 g, 4.degree. C. The pellets were resuspended in binding
buffer (200 mM TRIS-HCl, 20 mM HEPES, pH 7.5, 144 mM NaCl, 1.5 mM
KCl, 1 mM MgSO.sub.4, 2 mM CaCl.sub.2, 0.1% (w/v) BSA) and stored
membrane prep at -80.degree. C.
[0412] For saturation assay, the 200 .mu.l assay mixture in binding
buffer contains 200 .mu.g of membrane protein, 0.2 to 44 nM of
[.sup.3H]MLA. The nonspecific binding was defined using 1 .mu.M
MLA. Competition assay was carried out with 2 nM [.sup.3H]MLA and a
desirable range of compounds. The assay mixture was incubated at
22.degree. C. for 2 hours, then harvested with GF/B filter
presoaked with 0.3% PEI in binding buffer using Tomtec harvester.
The filter was washed three time with binding buffer and the
radioactivity was counted with Trilux.
[0413] Binding affinities for the preferred compounds of the
invention are 1 nM to 10 .mu.M, especially 250 nM to 8 .mu.M.
[0414] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0415] While the invention has been illustrated with respect to the
production and of particular compounds, it is apparent that
variations and modifications of the invention can be made without
departing from the spirit or scope of the invention.
* * * * *