U.S. patent application number 12/622548 was filed with the patent office on 2010-04-15 for tricyclic delta opioid modulators.
Invention is credited to Steven J. Coats, Scott L. Dax, Bart DeCorte, Li Liu, Mark McDonnell, James J. McNally.
Application Number | 20100093709 12/622548 |
Document ID | / |
Family ID | 36481352 |
Filed Date | 2010-04-15 |
United States Patent
Application |
20100093709 |
Kind Code |
A1 |
Coats; Steven J. ; et
al. |
April 15, 2010 |
TRICYCLIC DELTA OPIOID MODULATORS
Abstract
The invention is directed to delta opioid receptor modulators.
More specifically, the invention relates to tricyclic
.delta.-opioid modulators. Pharmaceutical and veterinary
compositions and methods of treating mild to severe pain and
various diseases using compounds of the invention are also
described.
Inventors: |
Coats; Steven J.;
(Quaketown, PA) ; Dax; Scott L.; (Landenberg,
PA) ; DeCorte; Bart; (Southhampton, PA) ; Liu;
Li; (Doylestown, PA) ; McDonnell; Mark;
(Lansdale, PA) ; McNally; James J.; (Souderton,
PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
36481352 |
Appl. No.: |
12/622548 |
Filed: |
November 20, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12248150 |
Oct 9, 2008 |
7652005 |
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12622548 |
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Current U.S.
Class: |
514/225.2 ;
514/229.8; 544/102; 544/42; 544/46 |
Current CPC
Class: |
C07D 451/04 20130101;
A61P 13/00 20180101; A61P 1/04 20180101; A61P 15/00 20180101; A61P
25/32 20180101; A61P 29/00 20180101; A61P 11/00 20180101; A61P
37/06 20180101; A61P 1/12 20180101; A61P 25/04 20180101; A61P 9/00
20180101; A61P 25/30 20180101; A61P 25/18 20180101; A61P 25/00
20180101 |
Class at
Publication: |
514/225.2 ;
544/102; 544/46; 544/42; 514/229.8 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; C07D 413/02 20060101 C07D413/02; C07D 413/14 20060101
C07D413/14; C07D 417/14 20060101 C07D417/14; A61K 31/538 20060101
A61K031/538 |
Claims
1. A method of providing analgesia comprising administering to a
patient a compound of Formula (I): ##STR00124## wherein: G is
--C(Z)N(R.sub.1)R.sub.2, C.sub.6-10aryl, or a heterocycle selected
from the group consisting of imidazolyl, triazolyl, tetrazolyl,
oxadiazolyl, thiadiazolyl, oxathiadiazolyl, imidazolinyl,
tetrahydropyrimidinyl, thienyl, pyrazolyl, pyrimidinyl, triazinyl,
furyl, indazolyl, indolyl, indolinyl, isothiazolyl, isoxazolyl,
oxazolyl, isoxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,
and pyridinyl; wherein aryl and the heterocycles of G are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.1-8alkanyloxy,
hydroxy(C.sub.1-8)alkanyl, carboxy(C.sub.1-8)alkanyl,
C.sub.1-galkanylcarbonylamino, halogen, hydroxy, cyano, nitro, oxo,
thioxo, amino, C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl,
C.sub.1-8alkanylsulfonylamino, aminocarbonyl, aminothiocarbonyl,
aminocarbonylamino, aminothiocarbonylamino,
C.sub.1-8alkanylaminocarbonyl, di(C.sub.1-8alkanyl)aminocarbonyl,
and C.sub.1-6alkanyloxycarbonylamino; R.sub.1 is a substituent
selected from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, and C.sub.2-8alkynyl; R.sub.2 is a substituent
selected from the group consisting of hydrogen; C.sub.1-8alkanyl;
C.sub.2-8alkenyl; C.sub.2-8alkynyl; C.sub.6-10aryl; and
C.sub.1-8cycloalkanyl; wherein C.sub.1-8alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, amino, C.sub.1-6 alkanylamino,
di(C.sub.1-6 alkanyl)amino, C.sub.1-6 alkanyloxy,
thioC.sub.1-6alkanyloxy, hydroxy, fluoro, chloro, cyano,
aminocarbonyl, C.sub.1 -8 alkanylaminocarbonyl, di(C.sub.1-8
alkanyl)aminocarbonyl, C.sub.1-6alkanyloxycarbonyl, and aryloxy;
and wherein any aryl-containing substituents and
C.sub.1-8cycloalkanyl substituents of R.sub.2 are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkanyloxy, trifluoromethyl,
trifluoromethoxy, phenyl, halogen, cyano, hydroxy, C.sub.1-8
alkanylthio, C.sub.1-8 alkanylsulfonyl, and
C.sub.1-8alkanylsulfonylamino; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, hydroxy(C.sub.1-8)alkanyl, hydroxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6 alkanyl)amino, and halogen;
R.sub.3 is a substituent selected from the group consisting of
hydrogen, C.sub.1-8alkanyl, halo.sub.1-3(C.sub.1-8)alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3 -8cycloalkanyl,
cycloalkanyl(C.sub.1-8)alkanyl, C.sub.1
-8alkanyloxy(C.sub.1-8)alkanyl, C.sub.1-8
alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1 -8alkanyl,
C.sub.1-8alkanyloxycarbonyl,
halo.sub.1-3(C.sub.1-8)alkanylcarbonyl, formyl, thioformyl,
carbamimidoyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkenyl,
phenyl(C.sub.1-8)alkynyl, naphthyl(C.sub.1-8)alkanyl and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl,
isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,
quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl,
naphthyl, and heteroaryl are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl, C.sub.2-6 alkenyl, C.sub.1 -6alkanyloxy,
amino, C.sub.1 -6alkanylamino, di(C.sub.1-6 alkanyl)amino,
C.sub.1-6alkanylcarbonyl, C.sub.1-6alkanylcarbonyloxy,
C.sub.1-6alkanylcarbonylamino, C.sub.1-6alkanylthio,
C.sub.1-6alkanylsulfonyl, halogen, hydroxy, cyano,
fluoro(C.sub.1-6)alkanyl, thioureido, and
fluoro(C.sub.1-6)alkanyloxy; alternatively, when phenyl and
heteroaryl are optionally substituted with alkanyl or alkanyloxy
substituents attached to adjacent carbon atoms, the two
substituents can together form a fused cyclic alkanyl or
cycloheteroalkanyl selected from the group consisting of
--(CH.sub.2).sub.3-5--, --O(CH.sub.2).sub.2-4--,
--(CH.sub.2).sub.2-4O--, and --O(CH.sub.2).sub.1-3O--; R.sub.4 is
one to three substituents independently selected from the group
consisting of hydrogen; C.sub.1-6alkanyl; C.sub.2-6alkenyl;
C.sub.2-6alkynyl; aryl(C.sub.2-6)alkynyl; C.sub.1-6alkanyloxy;
amino; C.sub.1-6alkanylamino; di(C.sub.1-6alkanyl)amino;
C.sub.6-10arylamino wherein C.sub.6-10aryl is optionally
substituted with one to three substitutents independently selected
from the group consisting of C.sub.1-6alkanyl, C.sub.1-6alkoxy,
halogen, and hydroxy; formylamino; pyridinylamino;
C.sub.1-6alkanylcarbonyl; C.sub.1 -6alkanylcarbonyloxy;
C.sub.1-6alkanyloxycarbonyl; aminocarbonyl;
C.sub.1-6alkanylaminocarbonyl; di(C.sub.1-6alkanyl)aminocarbonyl;
C.sub.1 -6alkanylcarbonylamino; C.sub.1-6alkanylthio;
C.sub.1-6alkanylsulfonyl; halogen; hydroxy; cyano; hydroxycarbonyl;
C.sub.6-10aryl; chromanyl; chromenyl; furanyl; imidazolyl;
indazolyl; indolyl; indolinyl; isoindolinyl; isoquinolinyl;
isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl; pyrazinyl;
pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl; pyrrolyl;
quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl; tetrazolyl;
thiazolyl; thienyl; fluoroalkanyl and fluoroalkanyloxy; or
optionally; when R.sub.4 is two substituents attached to adjacent
carbon atoms, the two substituents together form a single fused
moiety; wherein the fused moiety is --(CH.sub.2).sub.3-5--,
--O(CH.sub.2).sub.2-4--, --(CH.sub.2).sub.2-4O--,
--O(CH.sub.2).sub.1-3O--, or --S--C(NH.sub.2).dbd.N--; R.sub.5 is
one to two substituents independently selected from the group
consisting of hydrogen, C.sub.1-6alkanyl, C.sub.2-6alkenyl,
C.sub.1-6alkanyloxy, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-6alkanylcarbonyl,
C.sub.1-6alkanylcarbonyloxy, C.sub.1-6alkanyloxycarbonyl,
C.sub.1-6alkanylamino carbonyl, C.sub.1-6alkanylcarbonylamino,
C.sub.1-6alkanylthio, C.sub.1-6alkanylsulfonyl, halogen, hydroxy,
cyano, fluoro(C.sub.1-6)alkanyl and fluoro(C.sub.1-6)alkanyloxy; A
is --(CH.sub.2).sub.m--, wherein m is 2 or 3; Y is O; Z is O, S,
NH, N(C.sub.1-6alkanyl), N(OH), N(OC.sub.1-6alkanyl), or N(phenyl);
and enantiomers, diastereomers, tautomers, or pharmaceutically
acceptable salts thereof.
2. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadizolyl, furyl, quinolinyl,
thienyl, and pyridinyl; wherein phenyl and the heterocycles of G
are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, ydroxyl(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
ydroxyl, cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino.
3. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, imidazolinyl, tetrahydropyrimidinyl,
thienyl, pyrazolyl, pyrimidinyl, triazinyl, isothiazolyl,
isoxazolyl, oxazolyl, isoxadiazolyl, and pyridinyl; wherein phenyl
and the heterocycles of G are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
ydroxyl(C.sub.1-8)alkanyl, carboxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylcarbonylamino, halogen, ydroxyl, cyano, oxo,
thioxo, amino, C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-8alkanylthio, aminocarbonyl, aminothiocarbonyl,
C.sub.1-8alkanylaminocarbonyl, di(C.sub.1-8alkanyl)aminocarbonyl,
and C.sub.1-6alkanyloxycarbonylamino.
4. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, ydroxyl(C.sub.1-4)alkanyl,
carboxy(C.sub.1-4)alkanyl, C.sub.1-4alkanylcarbonylamino, ydroxyl,
cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl, and
di(C.sub.1-8alkanyl)aminocarbonyl.
5. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, thienyl, isothiazolyl, isoxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, ydroxyl(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, ydroxyl, cyano, oxo, thioxo, and
aminocarbonyl.
6. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadizolyl, furyl, quinolinyl,
thienyl, and pyridinyl; wherein phenyl and the heterocycles of G
are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, ydroxyl(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, ydroxyl, cyano, oxo, thioxo, and
aminocarbonyl.
7. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, tetrazolyl, pyridinyl, oxadiazolyl
optionally substituted with oxo, or phenyl optionally substituted
with (C.sub.1-8)alkanylcarbonylamino.
8. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, 1H-tetrazol-4-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 2-methylcarbonylaminophenyl,
pyridine-3-yl or pyridine-4-yl.
9. The method according to claim 1 wherein R.sub.1is a substituent
selected from the group consisting of hydrogen and
C.sub.1-4alkanyl.
10. The method according to claim 1 wherein R.sub.1 is selected
from the group consisting of hydrogen, methyl, ethyl, and
propyl.
11. The method according to claim 1 wherein R.sub.1is selected from
the group consisting of hydrogen, methyl, and ethyl.
12. The method according to claim 1 wherein R.sub.2 is selected
from the group consisting of hydrogen; C.sub.1-4alkanyl; phenyl;
and C.sub.1-6cycloalkanyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-4alkanyloxy, hydroxy, fluoro,
chloro, cyano, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and phenoxy; and wherein any
phenyl-containing substituents and C.sub.1-6cycloalkanyl
substituents of R.sub.2 are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, trifluoromethyl, phenyl,
fluoro, hydroxy, C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl,
and C.sub.1-8alkanylsulfonylamino; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkanyl, hydroxy(C.sub.1-4)alkanyl, hydroxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino, and fluoro.
13. The method according to claim 1 wherein R.sub.2 is selected
from the group consisting of hydrogen, C.sub.1-4alkanyl, phenyl,
and C.sub.1-6cycloalkanyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, C.sub.1-4alkanyloxy, hydroxy,
fluoro, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and phenoxy; and wherein any
phenyl-containing substituent of R.sub.2 is optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro,
hydroxy, and C.sub.1-6alkanylthio; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a
pyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl or
piperidinyl is optionally substituted with a substituent selected
from the group consisting of C.sub.1-4alkanyl and hydroxy.
14. The method according to claim 1 wherein R.sub.2 is selected
from the group consisting of hydrogen, C.sub.1-4alkanyl and phenyl;
wherein C.sub.1-4alkanyl is optionally substituted with one to
three substituents independently selected from the group consisting
of phenyl, C.sub.1-4alkanyloxy, hydroxy, fluoro, and phenoxy; and
wherein any phenyl-containing substituent of R.sub.2 is optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl, C.sub.1-6alkanyloxy,
fluoro, and hydroxy; or R.sub.1 and R.sub.2 taken together with the
nitrogen to which they are attached form a pyrrolidinyl or
piperidinyl ring wherein said pyrrolidinyl or piperidinyl is
optionally substituted with a substituent selected from the group
consisting of C.sub.1-3alkanyl and hydroxy.
15. The method according to claim 1 wherein R.sub.2 is selected
from the group consisting of hydrogen and C.sub.1-4alkanyl; wherein
C.sub.1-4alkanyl is optionally substituted with phenyl; or R.sub.1
and R.sub.2 taken together with the nitrogen to which they are
attached form a pyrrolidinyl wherein said pyrrolidinyl is
optionally substituted with hydroxy.
16. The method according to claim 1 wherein R.sub.2 is selected
from the group consisting of hydrogen, methyl, ethyl, and
phenethyl; or R.sub.1 and R.sub.2 taken together with the nitrogen
to which they are attached form pyrrolidin-1-yl,
3-hydoxypyrrolidin-1-yl or 3-(S)-hydoxypyrrolidin-1-yl.
17. The method according to claim 1 wherein R.sub.3 is selected
from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
thioformyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, and heteroaryl(C.sub.1-8)alkanyl wherein
heteroaryl is selected from the group consisting of
benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,
indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,
tetrazolyl; wherein phenyl and heteroaryl are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyloxy and hydroxy; or
optionally, when phenyl and heteroaryl are optionally substituted
with two substituents attached to adjacent carbon atoms, the two
substituents together form a single fused moiety; wherein the
moiety is selected from --O(CH.sub.2).sub.1-3O--.
18. The method according to claim 1 wherein R.sub.3 is selected
from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
thioformyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, and heteroaryl(C.sub.1-8)alkanyl wherein
heteroaryl is selected from the group consisting of
benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,
indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl,
isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyloxy and
hydroxy; or optionally, when phenyl and heteroaryl are optionally
substituted with two substituents attached to adjacent carbon
atoms, the two substituents together form a single fused moiety;
wherein the moiety is selected from --O(CH.sub.2).sub.1-3O--.
19. The method according to claim 1 wherein R.sub.3 is selected
from the group consisting of hydrogen, methyl, allyl,
2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,
methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,
isoquinolinyl, tetrazolyl; wherein the phenyl in any
phenyl-containing substituent is optionally substituted with one
hydroxyl group.
20. The method according to claim 1 wherein R.sub.3 is selected
from the group consisting of hydrogen, methyl, methylbutenyl,
propenyl, benzyl, phenethyl, and heteroaryl(C.sub.1-8)alkanyl
wherein the heteroaryl is selected from the group consisting of
imidazolyl, furanyl, pyridinyl, thienyl, and thiazolyl.
21. The method according to claim 1 wherein R.sub.3 is selected
from the group consisting of hydrogen, methyl, 3-methyl-2-butenyl,
2-propenyl, benzyl, 2-phenethyl, pyridin-2-ylmethyl,
fur-3-ylmethyl, thiophene-2-ylmethyl, 1H-imidazol-2-ylmethyl, and
thiazol-2-ylmethyl.
22. The method according to claim 1 wherein R.sub.3 is hydrogen,
methyl, allyl, or heteroarylmethyl wherein heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, and thienyl.
23. The method according to claim 1 wherein R.sub.4 is one to three
substituents independently selected from the group consisting of
hydrogen; C.sub.1-6alkanyl; C.sub.1-6alkanyloxy;
C.sub.6-10arylamino wherein C.sub.6-10aryl is optionally
substituted with one to three substitutents independently selected
from the group consisting of C.sub.1-6alkanyl; C.sub.1-6alkoxy,
halogen, and hydroxy; formylamino; pyridinylamino; aminocarbonyl;
C.sub.1-6alkanylaminocarbonyl; C.sub.1-6alkanylcarbonylamino;
halogen; hydroxy; C.sub.6-10aryl; chromanyl; chromenyl; furanyl;
imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; and thienyl.
24. The method according to claim 1 wherein R.sub.4 is one to two
substituents independently selected from the group consisting of
hydrogen, C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, halogen, phenyl,
furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy.
25. The method according to claim 1 wherein R.sub.4 is one to two
substituents independently selected from the group consisting of
hydrogen, methyl, methoxy, bromo, fluoro, .alpha.'- or
.beta.'-phenyl, .alpha.'- or .beta.'-pyridinyl, .alpha.'- or
.beta.'-furanyl, and hydroxy.
26. The method according to claim 1 wherein R.sub.4 is one to two
substituents independently selected from the group consisting of
hydrogen, methyl, phenyl, bromo, fluoro, methoxy, aminocarbonyl,
chloro and hydroxy.
27. The method according to claim 1 wherein R.sub.4 is hydrogen,
.alpha.'-methoxy, or .alpha.'-hydroxy.
28. The method according to claim 1 wherein R.sub.4 is
hydrogen.
29. The method according to claim 1 wherein R.sub.4 is
.alpha.'-hydroxy.
30. The method according to claim 1 wherein R.sub.5 is one to two
substituents independently selected from the group consisting of
hydrogen and halogen.
31. The method according to claim 1 wherein R.sub.5 is
hydrogen.
32. The method according to claim 1 wherein A is
--(CH.sub.2).sub.2-3--.
33. The method according to claim 1 wherein A is
--(CH.sub.2).sub.2--.
34. The method according to claim 1 wherein Z is O, NH,
N(C.sub.1-6alkanyl), N(OH), N(OC.sub.1-6alkanyl), or N(phenyl).
35. The method according to claim 1 wherein Z is O, NH, or
N(OH).
36. The method according to claim 1 wherein Z is O or NH.
37. The method according to claim 1 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadizolyl, furyl, quinolinyl,
thienyl, or pyridinyl; wherein phenyl and the heterocycles of G are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; R.sub.1 is C.sub.1-4alkanyl, or
hydrogen; R.sub.2 is hydrogen or C.sub.1-4alkanyl optionally
substituted with phenyl; or R.sub.1 and R.sub.2 taken together with
the nitrogen to which they are attached form a pyrrolidinyl ring
optionally substituted with hydroxy; Z is NH or oxygen; R.sub.3 is
pyridinyl(C.sub.1-8)alkanyl, furyl(C.sub.1-8)alkanyl, C.sub.1-8
alkanyl, hydrogen, C.sub.2-8 alkenyl, thienyl(C.sub.1-8)alkanyl,
imidazolyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkanyl, or
thiazolyl(C.sub.1-8)alkanyl; R.sub.4 is hydrogen, C.sub.1-6alkanyl,
C.sub.1-6alkanyloxy, hydroxy, halogen, aminocarbonyl, or phenyl;
R.sub.5 is hydrogen; A is CH.sub.2CH.sub.2; Z is O or NH; and
enantiomers, diastereomers, tautomers, and pharmaceutically
acceptable salts thereof.
38. The method according to claim 37 wherein G is
--C(Z)N(R.sub.1)R.sub.2; tetrazolyl; oxadiazolyl optionally
substituted with oxo; furyl; quinolinyl; thienyl; phenyl optionally
substituted with (C.sub.1-8)alkanylcarbonylamino; or pyridinyl.
39. The method according to claim 38 wherein when R.sub.1 and
R.sub.2 taken together with the nitrogen to which they are attached
form a pyrrolidinyl ring optionally substituted with hydroxy, Z is
oxygen
40. The method according to claim 1 wherein: G is
--C(Z)N(R.sub.1)R.sub.2; tetrazolyl; oxadiazolyl optionally
substituted with oxo; phenyl optionally substituted with
(C.sub.1-8)alkanylcarbonylamino; or pyridinyl; R.sub.1 is C.sub.1-4
alkanyl, or hydrogen; R.sub.2 is hydrogen or C.sub.1-4 alkanyl
optionally substituted with phenyl; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a
pyrrolidinyl ring optionally substituted with hydroxyl; Z is NH or
oxygen; R.sub.3 is pyridinyl(C.sub.1-8)alkanyl,
furyl(C.sub.1-8)alkanyl, C.sub.1-8 alkanyl, hydrogen, C.sub.2-8
alkenyl, thienyl(C.sub.1-8)alkanyl, imidazolyl(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, or thiazolyl(C.sub.1-8)alkanyl; R.sub.4
is hydrogen, .alpha.'-hydroxy, or .alpha.'-methoxy; R.sub.5 is
hydrogen; A is CH.sub.2CH.sub.2; Z is O or NH; and enantiomers,
diastereomers, tautomers, and pharmaceutically acceptable salts
thereof.
41. The method according to claim 1 wherein: G is
--C(Z)N(R.sub.1)R.sub.2, 1H-tetrazol-4-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 2-methylcarbonylaminophenyl,
pyridin-3-yl or pyridin-4-yl, R.sub.1 is hydrogen, ethyl, or
methyl, R.sub.2 is methyl, ethyl, phenethyl, or hydrogen; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, or
3-(S)-hydroxypyrrolidin-1-yl; Z is NH or oxygen, R.sub.3 is
pyridin-2-ylmethyl, fur-3-ylmethyl, methyl, hydrogen,
3-methyl-2-butenyl, thiophene-2-ylmethyl, 2-propenyl,
1H-imidazol-2-ylmethyl, 2-phenethyl, thiazol-2-ylmethyl, benzyl,
R.sub.4 is hydrogen, .alpha.'-methoxy, or .alpha.'-hydroxy, R.sub.5
is hydrogen A is CH.sub.2CH.sub.2; Z is O or NH; and enantiomers,
diastereomers, tautomers, and pharmaceutically acceptable salts
thereof.
42. A method of providing analgesia comprising administering to a
patient a compound of Formula (I): ##STR00125## wherein: G is
independently selected from --C(Z)N(R.sub.1)R.sub.2, phenyl, or a
heterocycle selected from the group consisting of imidazolyl,
triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,
imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; provided that when G is
pyridin-3-yl or thien-3-yl and R.sup.3 is hydrogen, R.sup.4 is
other than hydrogen; R.sub.1 is hydrogen or C.sub.1-4alkanyl;
R.sub.2 is selected from the group consisting of hydrogen;
C.sub.1-4alkanyl; phenyl; and C.sub.1-6cycloalkanyl; wherein
C.sub.1-4alkanyl is optionally substituted with one to three
substituents independently selected from the group consisting of
phenyl, amino, C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-4alkanyloxy, hydroxy, fluoro, chloro, cyano, aminocarbonyl,
C.sub.1-8alkanylaminocarbonyl, di(C.sub.1-8alkanyl)aminocarbonyl,
and phenoxy; and wherein any phenyl-containing substituent of
R.sub.2 and C.sub.1-6cycloalkanyl substituents of R.sub.2 are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, trifluoromethyl, phenyl, fluoro, hydroxy,
C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl, and
C.sub.1-8alkanylsulfonylamino; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered heterocycloalkyl wherein said heterocycloalkyl is
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl,
hydroxy(C.sub.1-8)alkanyl, and hydroxy; R.sub.3 is selected from
the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylthio
(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl, thioformyl,
phenylimino(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkanyl, and
heteroaryl(C.sub.1-8)alkanyl wherein heteroaryl is selected from
the group consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl,
pyridinyl, thienyl, indolyl, indolinyl, isoquinolinyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl,
isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyloxy and
hydroxy; or optionally, when phenyl and heteroaryl are optionally
substituted with two substituents attached to adjacent carbon
atoms, the two substituents together form a single fused moiety;
wherein the moiety is selected from --O(CH.sub.2).sub.1-3O--;
R.sub.4 is one to three substituents independently selected from
the group consisting of hydrogen; C.sub.1-6alkanyl;
C.sub.1-6alkanyloxy; C.sub.6-10arylamino wherein C.sub.6-10aryl is
optionally substituted with one to three substitutents
independently selected from the group consisting of
C.sub.1-6alkanyl; C.sub.1-6alkoxy, halogen, and hydroxy;
formylamino; pyridinylamino; aminocarbonyl;
C.sub.1-6alkanylaminocarbonyl; C.sub.1-6alkanylcarbonylamino;
halogen; hydroxy; C.sub.6-10aryl; chromanyl; chromenyl; furanyl;
imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; and thienyl; R.sub.5 is one to two
substituents independently selected from the group consisting of
hydrogen and halogen; A is CH.sub.2CH.sub.2; Y is O; Z is O, NH,
N(C.sub.1-6alkanyl), N(OH), N(OC.sub.1-6alkanyl), or N(phenyl); and
enantiomers, diastereomers, tautomers, and pharmaceutically
acceptable salts thereof.
43. A method of providing analgesia comprising administering a
compound of Formula (I): ##STR00126## wherein: G is selected from
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, hydroxy(C.sub.1-4)alkanyl,
carboxy(C.sub.1-4alkanyl, C.sub.1-4alkanylcarbonylamino, hydroxy,
cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl, and
di(C.sub.1-8alkanyl)aminocarbonyl; R.sub.1 is selected from the
group consisting of hydrogen, methyl, ethyl, and propyl; R.sub.2 is
selected from the group consisting of hydrogen, C.sub.1-4alkanyl,
phenyl, and C.sub.1-6cycloalkanyl; wherein C.sub.1-4alkanyl is
optionally substituted with one to three substituents independently
selected from the group consisting of phenyl, C.sub.1-4alkanyloxy,
hydroxy, fluoro, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and phenoxy; and wherein any
phenyl-containing substituent of R.sub.2 is optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro,
hydroxy, and C.sub.1-6alkanylthio; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form
pyrrolidinyl or piperidinyl ring wherein said pyrrolidinyl or
piperidinyl is optionally substituted with a substituent selected
from the group consisting of C.sub.1-3alkanyl and hydroxy; R.sub.3
is selected from the group consisting of hydrogen, methyl, allyl,
2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,
methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,
isoquinolinyl, tetrazolyl; wherein the phenyl in any
phenyl-containing substituent is optionally substituted with one
hydroxyl group; R.sub.4 is one to two substituents independently
selected from the group consisting of hydrogen, C.sub.1-4alkanyl,
C.sub.1-4alkanyloxy, halogen, phenyl, furanyl, imidazolyl,
indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,
isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl,
tetrazolyl, thiazolyl, thienyl, and hydroxy; R.sub.5 is hydrogen; A
is CH.sub.2CH.sub.2; Y is O; Z is O, NH, or N(OH); and enantiomers,
diastereomers, tautomers, and pharmaceutically acceptable salts
thereof.
44. The method according to claim 43 wherein G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, thienyl, isothiazolyl, isoxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, hydroxy(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, and
aminocarbonyl.
44. The method according to claim 43 wherein G is
--C(Z)N(R.sub.1)R.sub.2, 2-methylcarbonylaminophenyl,
2-aminocarbonyl-phenyl, 1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,
4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl,
or pyridin-3-yl.
45. The method according to claim 43 wherein G is
--C(Z)N(R.sub.1)R.sub.2, 1H-tetrazol-4-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 2-methylcarbonylaminophenyl,
pyridin-3-yl or pyridin-4-yl.
46. The method according to claim 43 wherein R.sub.2 is selected
from the group consisting of hydrogen, C.sub.1-4alkanyl and phenyl;
wherein C.sub.1-4alkanyl is optionally substituted with one to
three substituents independently selected from the group consisting
of phenyl, C.sub.1-4alkanyloxy, hydroxy, fluoro, and phenoxy; and
wherein any phenyl-containing substituent is optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro,
and hydroxy; or R.sub.1 and R.sub.2 taken together with the
nitrogen to which they are attached form a pyrrolidinyl or
piperidinyl ring wherein said pyrrolidinyl or piperidinyl is
optionally substituted with a substituent selected from
C.sub.1-3alkanyl or hydroxy; and R.sub.3 is a substituent selected
from the group consisting of benzo[1,3]dioxol-5-ylmethyl,
carbamimidoyl, 1-H-imidazol-4-ylmethyl, phenyliminomethyl,
1-prop-2-ynyl, thioformyl, 2-hydroxyphenyl-methyl, hydroxy-ethyl,
methoxy-ethyl, 2-methyl-allyl, 2-methyl-but-2-enyl, allyl,
furan-3-ylmethyl, H, Me, methylthioethyl, phenethyl, pyridin-2-yl
methyl, and thiophen-2-yl methyl.
47. The method according to claim 43 wherein R.sub.1 is hydrogen,
ethyl, or methyl; R.sub.2 is methyl, ethyl, phenethyl, or hydrogen;
or R.sub.1 and R.sub.2 taken together with the nitrogen to which
they are attached form pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,
or 3-(S)-hydroxypyrrolidin-1-yl.
48. A method of providing analgesia comprising administering to a
patient a compound of Formula (I): ##STR00127## wherein: G is
selected from --C(Z)N(R.sub.1)R.sub.2, 2-methylcarbonylaminophenyl,
2-aminocarbonyl-phenyl, 1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl,
4H- [1,2,4]-oxadiazol-5-oxo-3-yl,
4H-[1,2,4]-oxadiazol-5-thioxo-3-yl, 4H-
[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl, or
pyridin-3-yl; R.sub.1is hydrogen, methyl, or ethyl; R.sub.2 is
selected from the group consisting of hydrogen, C.sub.1-4alkanyl
and phenyl; wherein C.sub.1-4alkanyl is optionally substituted with
one to three substituents independently selected from the group
consisting of phenyl, C.sub.1-4alkanyloxy, hydroxy, fluoro, and
phenoxy; and wherein any phenyl-containing substituent of R.sub.2
is optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a pyrrolidinyl or piperidinyl ring wherein said
pyrrolidinyl or piperidinyl is optionally substituted with a
substituent selected from C.sub.1-3alkanyl or hydroxy; R.sub.3 is
selected from the group consisting of hydrogen, methyl, allyl,
2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,
methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,
isoquinolinyl, tetrazolyl; wherein the phenyl in any
phenyl-containing substituent is optionally substituted with one
hydroxyl group; R.sub.4 is one to three substituents independently
selected from the group consisting of hydrogen, C.sub.1-4alkanyl,
C.sub.1-4alkanyloxy, halogen, phenyl, furanyl, imidazolyl,
indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,
isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl,
tetrazolyl, thiazolyl, thienyl, and hydroxy; R.sub.5 is hydrogen; A
is CH.sub.2CH.sub.2; Y is O; Z is O or NH; and enantiomers,
diastereomers, tautomers, and pharmaceutically acceptable salts
thereof.
49. The method according to claim 48 wherein R.sub.2 is a
substituent selected from the group consisting of hydrogen,
C.sub.1-4alkanyl and phenyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, C.sub.1-4alkanyloxy, hydroxy,
and 2,6-dimethyl-phenoxy; and wherein any phenyl-containing
substituent of R.sub.2 is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a pyrrolidinyl or piperidinyl ring wherein said
pyrrolidinyl or piperidinyl is optionally substituted with a
substituent selected from C.sub.1-3alkanyl or hydroxy.
50. The method according to claim 48 wherein R.sub.3 is a
substituent selected from the group consisting of
benzo[1,3]dioxol-5-ylmethyl, carbamimidoyl,
1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl,
thioformyl, 2-hydroxyphenyl-methyl, hydroxy-ethyl, methoxy-ethyl,
2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H,
Me, methylthioethyl, phenethyl, pyridin-2-yl methyl, and
thiophen-2-ylmethyl; and R.sub.4 is one to two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, halogen, phenyl, furanyl,
imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy.
51. The method according to claim 48 wherein R.sub.3 is a
substituent selected from the group consisting of
benzo[1,3]dioxol-5-ylmethyl, carbamimidoyl, 1-H-imidazol-4-yl
methyl, phenyliminomethyl, 1-prop-2-ynyl, thioformyl,
2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl, allyl,
furan-3-yl methyl, H, Me, methylthioethyl, and phenethyl; R.sub.4
is one to two substituents independently selected from the group
consisting of hydrogen, methyl, methoxy, bromo, fluoro, .alpha.'-
or .beta.'-phenyl, .alpha.'- or .beta.'-pyridinyl, .alpha.'- or
.beta.'-furanyl, and hydroxy.
52. The method according to claim 48 wherein R.sub.3 is a
substituent selected from the group consisting of H,
benzo[1,3]dioxol-5-ylmethyl, 1-H-imidazol-4-yl methyl,
furan-3-ylmethyl, pyridin-2-ylmethyl, and phenyliminomethyl; and
R.sub.4 is a substituent independently selected from the group
consisting of hydrogen, methyl, methoxy, bromo, fluoro, .alpha.'-
or .beta.'-phenyl, .alpha.'- or .beta.'-pyridinyl, .alpha.'- or
.beta.'-furanyl, and hydroxy.
53. A method of providing analgesia comprising administering to a
patient a compound of Formula (I): ##STR00128## selected from the
group consisting of: a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is 1H-imidazol-2-yl-methyl;
R.sup.4 is .alpha.'-hydroxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is furan-3-yl-methyl; R.sup.4 is
.alpha.'-hydroxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
.alpha.'-hydroxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
.alpha.'-methoxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is pyridin-2-yl-methyl; R.sup.4
is H; R.sup.5 is H; Y is O; A is --CH.sub.2CH.sub.2--; a compound
of Formula (I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is
furan-3-yl-methyl; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is thien-2-yl-methyl; R.sup.4 is
H; R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; a compound
of Formula (I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is
benzyl; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
pyridin-3-yl; R.sup.3 is furan-3-y1 methyl; R.sup.4 is H; R.sup.5
is H; Y is O; and A is --CH.sub.2CH.sub.2--; a compound of Formula
(I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is furan-2-yl
methyl; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is .alpha.'-methyl;
R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; a compound of
Formula (I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is H;
R.sup.4 is .alpha.'-phenyl; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is H; R.sup.5 is H;
Y is O; and A is --CH.sub.2CH.sub.2--; a compound of Formula (I)
wherein G is N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is H;
R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; a compound of
Formula (I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is H;
R.sup.4 is .beta.''-bromo; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is H; R.sup.5 is H;
Y is O; and A is --CH.sub.2CH.sub.2--; a compound of Formula (I)
wherein G is N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
.alpha.'-chloro; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is .alpha.'-fluoro;
R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; a compound of
Formula (I) wherein G is 2-methylcarbonylamino-phenyl; R.sup.3 is
H; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G is
pyrrolidin-1-yl; R.sup.3 is H; R.sup.4 is H; R.sup.5 is H; Y is O;
and A is --CH.sub.2CH.sub.2--; a compound of Formula (I) wherein G
is N,N-diethylaminocarbonyl; R.sup.3 is furan-3-yl-methyl; R.sup.4
is H; R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; and a
compound of Formula (I) wherein G is N,N-diethylaminocarbonyl;
R.sup.3 is furan-3-yl-methyl; R.sup.4 is H; R.sup.5 is H; Y is O;
and A is --CH.sub.2CH.sub.2--.
54. A method according to claim 1 wherein the compound is:
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; (3
-Hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenoxazine-3-yl]-methanone;
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3
-carboxylic acid methyl-phenethyl-amide;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne;
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetr-
azol-5-yl)-10H-phenoxazine;
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-1-
0H-phenoxazine;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-10H-phenoxazine-3-carb-
oxamidine;
Endo-N,N-Diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl)-10H-phenoxazine-3-carboxamidine;
Endo-N,N-Diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenox-
azine-3-carboxamidine;
Endo-3-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-yl]-4H-[1,2,4-
]oxadiazol-5-one;
endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid amide; Endo-3-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-yl]-4H-[1,2,4]oxadiazol-5-one;
Endo-3-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-y-
l]-4H-[1,2,4]oxadiazol-5-one;
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide;
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide;
6-Methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide;
6-Hydroxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide;
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid diethylamide;
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-pheno-
xazine;
N,N-Diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxa-
zine-3-carboxamidine;
3-[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-yl]-4H-[1-
,2,4]oxadiazol-5-one;
10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-p-
henothiazine;
N-{2-[10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiaz-
ine-3-yl]-phenyl}-acetamide;
10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-3-yl--
10H-phenothiazine;
3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine;
10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-4-yl--
10H-phenothiazine;
3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine; or
3-Pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10-
H-phenothiazine.
55. A method according to claim 1 wherein the compound is:
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine;
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phe-
noxazine;
Endo-3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1-
]oct-3-yl)-10H-phenoxazine;
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl--
10H-phenoxazine;
Endo-3-Pyridin-3-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine;
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-
10H-phenoxazine;
Endo-3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
-10H-phenoxazine;
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl--
10-phenoxazine;
Endo-3-Pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine;
Exo-3-(3-Pyridin-3-yl-phenoxazine-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester;
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phen-
oxazine;
Exo-3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl)-10H-phenoxazine;
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-1-
0H-phenoxazine;
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine;
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phen-
oxazine;
Exo-3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl)-10H-phenoxazine;
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-1-
0H-phenoxazine;
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazin-
e; or Exo-3-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3
-yl]-4H-[1,2,4]oxadiazol-5-one;
56. A method according to claim 1 wherein the compound is:
Endo-10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxaz-
ine-3-carboxylic acid diethylamide;
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide;
Endo-10-(8-Thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide;
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carb-
oxylic acid diethylamide;
Endo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide;
Endo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenox-
azine-3-carboxylic acid diethylamide;
Endo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phe-
noxazine-3-carboxylic acid diethylamide;
Endo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxy-
lic acid diethylamide;
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide;
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbo-
xylic acid diethylamide;
Exo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide;
Exo-10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide;
Exo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenoxa-
zine-3-carboxylic acid diethylamide;
Exo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide;
Exo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxyl-
ic acid diethylamide; or
Exo-10-(8-Thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide.
57. A method according to claim 1 that is:
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine--
3-carboxylic acid diethylamide;
Exo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phen-
oxazine-3-carboxylic acid diethylamide;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenoxazine-4-o-
l;
Endo-7-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3--
yl)-10H-phenoxazine-4-ol;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-10H-pheno-
xazine;
Endo-6-Methoxy-3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyc-
lo[3.2.1]oct-3-yl)-10H-phenoxazine;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazin-4-ol-
;
Endo-7-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine-4-ol;
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phe-
noxazine-4-ol;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-4-yl-10H-pheno-
xazine;
Endo-6-Methoxy-3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyc-
lo[3.2.1]oct-3-yl)-10H-phenoxazine;
Endo-6-Methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4--
yl-10H-phenoxazine;
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-yl]-phenyl-
}-acetamide;
Endo-N-{2-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine--
3-yl]-phenyl}-acetamide;
Endo-N-{2-[10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enoxazine-3-yl]-phenyl}-acetamide;
Endo-N-{2-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phe-
noxazine-3-yl]-phenyl}-acetamide;
Exo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-
10H-phenoxazine-3-yl]-phenyl}-acetamide;
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenoxazine-3--
yl]-phenyl}-acetamide; or
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3--
yl]-phenyl}-acetamide.
58. A method according to claim 1 wherein the compound is:
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide;
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazo-
l-5-yl)-10H-phenoxazine;
Endo-3-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenox-
azine-3-yl]-4H-[1,2,4]oxadiazol-5-one;
Endo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phe-
noxazine-3-carboxylic acid diethylamide;
Endo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenox-
azine-3-carboxylic acid diethylamide;
Endo-7-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazine-4-ol;
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenoxazine-3--
yl]-phenyl}-acetamide;
Endo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxy-
lic acid diethylamide;
6-Hydroxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide;
Endo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide;
Exo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazine-4-o-
l;
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenoxazine-4-
-ol; or
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridi-
n-3-yl-10H-phenoxazine.
59. A method of providing analgesia comprising administering to a
patient a composition comprising the dextrorotatory enantiomer of a
compound according to claim 1 wherein said composition is
substantially free from the levorotatory isomer of said
compound.
60. A method of providing analgesia comprising administering to a
patient a composition comprising the levororotatory enantiomer of a
compound according to claim 1 wherein said composition is
substantially free from the dextrorotatory isomer of said
compound.
61. A method of providing analgesia comprising administering to a
patient a composition comprising the exo isomer of a compound
according to claim 1 wherein said composition is substantially free
from the endo isomer of said compound.
62. A method of providing analgesia comprising administering to a
patient a composition comprising the endo isomer of a compound
according to claim 1 wherein said composition is substantially free
from the exo isomer of said compound.
63. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to any of claims 1 admixed with a
pharmaceutically acceptable carrier, excipient or diluent.
64. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 1 admixed with a veterinarily acceptable
carrier, excipient or diluent.
65. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 42 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
66. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 42 admixed with a veterinarily
acceptable carrier, excipient or diluent.
67. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 43 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
68. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 43 admixed with a veterinarily
acceptable carrier, excipient or diluent.
69. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 48 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
70. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 48 admixed with a veterinarily
acceptable carrier, excipient or diluent.
71. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 53 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
72. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 53 admixed with a veterinarily
acceptable carrier, excipient or diluent.
73. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 54 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
74. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 54 admixed with a veterinarily
acceptable carrier, excipient or diluent.
75. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 55 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
76. A method of providing analgesia comprising administering to a
patient veterinary composition comprising a compound, salt or
solvate according to claim 55 admixed with a veterinarily
acceptable carrier, excipient or diluent.
77. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 59 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
78. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 59 admixed with a veterinarily
acceptable carrier, excipient or diluent.
79. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 60 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
80. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 60 admixed with a veterinarily
acceptable carrier, excipient or diluent.
81. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 61 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
82. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 61 admixed with a veterinarily
acceptable carrier, excipient or diluent.
83. A method of providing analgesia comprising administering to a
patient a pharmaceutical composition comprising a compound, salt or
solvate according to claim 62 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
84. A method of providing analgesia comprising administering to a
patient a veterinary composition comprising a compound, salt or
solvate according to claim 62 admixed with a veterinarily
acceptable carrier, excipient or diluent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit to U.S. Provisional
Application Ser. No. 60/638,315, filed Dec. 22, 2004, incorporated
herein by reference in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] The research and development of the invention described
below was not federally sponsored.
BACKGROUND
[0003] The term "opiate" has been used to designate
pharmacologically active alkaloids derived from opium, e.g.,
morphine, codeine, and many semi-synthetic congeners of morphine.
After the isolation of peptide compounds with morphine-like
actions, the term opioid was introduced to refer generically to all
drugs with morphine-like actions. Included among opioids are
various peptides that exhibit morphine-like activity, such as
endorphins, enkephalins and dynorphins. However, some sources use
the term "opiate" in a generic sense, and in such contexts, opiate
and opioid are interchangeable. Additionally, the term opioid has
been used to refer to antagonists of morphine-like drugs as well as
to characterize receptors or binding sites that combine with such
agents.
[0004] Opioids are generally employed as analgesics, but they may
have many other pharmacological effects as well. Morphine and
related opioids produce certain of their major effects on the
central nervous and digestive systems. The effects are diverse,
including analgesia, drowsiness, mood changes, respiratory
depression, dizziness, mental clouding, dysphoria, pruritus,
increased pressure in the biliary tract, decreased gastrointestinal
motility, nausea, vomiting, and alterations of the endocrine and
autonomic nervous systems.
[0005] When therapeutic doses of morphine are given to patients
with pain, they report that the pain is less intense, less
discomforting, or entirely gone. In addition to experiencing relief
of distress, some patients experience euphoria. However, when
morphine in a selected pain-relieving dose is given to a pain-free
individual, the experience is not always pleasant; nausea is
common, and vomiting may also occur. Drowsiness, inability to
concentrate, difficulty in mentation, apathy, lessened physical
activity, reduced visual acuity, and lethargy may ensue.
[0006] Two distinct classes of opioid molecules can bind opioid
receptors: the opioid peptides (e.g., the enkephalins, dynorphins,
and endorphins) and the alkaloid opiates (e.g., morphine,
etorphine, diprenorphine and naloxone). Subsequent to the initial
demonstration of opiate binding sites (Pert, C. B. and Snyder, S.
H., Science (1973) 179:1011-1014), the differential pharmacological
and physiological effects of both opioid peptide analogues and
alkaloid opiates served to delineate multiple opioid receptors.
Accordingly, three molecularly and pharmacologically distinct
opioid receptor types have been described: delta, kappa and mu.
Furthermore, each type is believed to have sub-types (Wollemann,
M., J Neurochem (1990) 54:1095-1101; Lord, J. A., et al., Nature
(1977) 267:495-499).
[0007] All three of these opioid receptor types appear to share the
same functional mechanisms at a cellular level. For example, the
opioid receptors cause inhibition of adenylate cyclase, and
inhibition of neurotransmitter release via both potassium channel
activation and inhibition of Ca.sup.2+ channels (Evans, C. J., In:
Biological Basis of Substance Abuse, S. G. Korenman & J. D.
Barchas, eds., Oxford University Press (in press); North, A. R., et
al., Proc Natl Acad Sci USA (1990) 87:7025-29; Gross, R. A., et
al., Proc Natl Acad Sci USA (1990) 87:7025-29; Sharma, S. K., et
al., Proc Natl Acad Sci USA (1975) 72:3092-96). Although the
functional mechanisms are the same, the behavioral manifestations
of receptor-selective drugs differ greatly (Gilbert, P. E. &
Martin, W. R., J Pharmacol Exp Ther (1976) 198:66-82). Such
differences may be attributable in part to the anatomical location
of the different receptors.
[0008] Delta receptors have a more discrete distribution within the
mammalian CNS than either mu or kappa receptors, with high
concentrations in the amygdaloid complex, striatum, substantia
nigra, olfactory bulb, olfactory tubercles, hippocampal formation,
and the cerebral cortex (Mansour, A., et al., Trends in Neurosci
(1988) 11:308-14). The rat cerebellum is remarkably devoid of
opioid receptors including delta opioid receptors.
[0009] D. Delorme, E. Roberts and Z. Wei, World Patent WO/28275
(1998) discloses diaryl methylidenylpiperidines that are opioid
analgesics, but does not disclose or suggest the compounds of the
present invention.
[0010] C. Kaiser, and others (J. Med. Chem. 1974, Volume 17, pages
57-61) disclose some piperidylidene derivatives of thioxanthenes,
xanthenes, dibenoxepins and acridans that are neuroleptic agents.
These authors, however, do not disclose or suggest either the
structure or the activity of the compounds of the present
invention.
[0011] British Patent GB 1128734 (1966) discloses derivatives of
6,11-dihydrodibenzo[b,e]oxepine that are anticholinergic,
anti-convulsive, muscle-relaxing, sedating, diuretic, and/or
vasoactive agents. These, agents, however, differ significantly
from the compounds of the present invention both structurally and
pharmacologically.
[0012] There is a continuing need for new delta opioid receptor
modulators as analgesics. There is a further need for delta opioid
receptor selective agonists as analgesics having reduced side
effects. There is also a need for delta opioid receptor antagonists
as immunosuppressants, antiinflammatory agents, agents for the
treatment of neurological and psychiatric conditions, agents for
the treatment of urological and reproductive conditions,
medicaments for drug and alcohol abuse, agents for treating
gastritis and diarrhea, cardiovascular agents and agents for the
treatment of respiratory diseases, having reduced side effects.
SUMMARY
[0013] The present invention is directed, inter alia, to compounds
of Formula (I) and compositions comprising a compound of Formula
(I):
##STR00001##
wherein: [0014] G is --C(Z)N(R.sub.1)R.sub.2, C.sub.6-10aryl, or a
heterocycle selected from the group consisting of imidazolyl,
triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,
imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, furyl, indazolyl, indolyl, indolinyl,
isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl,
quinolinyl, isoquinolinyl, and pyridinyl; wherein aryl and the
heterocycles of G are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, nitro, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio,
C.sub.1-8alkanylsulfonyl, C.sub.1-8alkanylsulfonylamino,
aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,
aminothiocarbonylamino, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; [0015] R.sub.1 is a substituent
selected from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, and C.sub.2-8alkynyl; [0016] R.sub.2 is a
substituent selected from the group consisting of hydrogen;
C.sub.1-8alkanyl; C.sub.2-8alkenyl; C.sub.2-8alkynyl;
C.sub.6-10aryl; and C.sub.1-8cycloalkanyl; wherein C.sub.1-8alkanyl
is optionally substituted with one to three substituents
independently selected from the group consisting of phenyl, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-6alkanyloxy, thioC.sub.1-6alkanyloxy, hydroxy, fluoro,
chloro, cyano, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, C.sub.1-6alkanyloxycarbonyl, and
aryloxy; and wherein any aryl-containing substituents and
C.sub.1-8cycloalkanyl substituents of R.sub.2 are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkanyloxy, trifluoromethyl,
trifluoromethoxy, phenyl, halogen, cyano, hydroxy,
C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl, and
C.sub.1-8alkanylsulfonylamino; [0017] or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, hydroxy(C.sub.1-8)alkanyl, hydroxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino, and halogen;
[0018] R.sub.3 is a substituent selected from the group consisting
of hydrogen, C.sub.1-8alkanyl, halo.sub.1-3(C.sub.1-8)alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkanyl,
cycloalkanyl(C.sub.1-8)alkanyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
C.sub.1-8alkanyloxycarbonyl,
halo.sub.1-3(C.sub.1-8)alkanylcarbonyl, formyl, thioformyl,
carbamimidoyl, phenylamino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkenyl,
phenyl(C.sub.1-8)alkynyl, naphthyl(C.sub.1-8)alkanyl and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl,
isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,
quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl,
naphthyl and heteroaryl are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl, C.sub.2-6alkenyl, C.sub.1-6alkanyloxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-6alkanylcarbonyl, C.sub.1-6alkanylcarbonyloxy,
C.sub.1-6alkanylcarbonylamino, C.sub.1-6alkanylthio,
C.sub.1-6alkanylsulfonyl, halogen, hydroxy, cyano,
fluoro(C.sub.1-6)alkanyl, thioureido, and
fluoro(C.sub.1-6)alkanyloxy; alternatively, when phenyl and
heteroaryl are optionally substituted with alkanyl or alkanyloxy
substituents attached to adjacent carbon atoms, the two
substituents can together form a fused cyclic alkanyl or
cycloheteroalkanyl selected from the group consisting of
--(CH.sub.2).sub.3-5--, --O(CH.sub.2).sub.2-4--,
--(CH.sub.2).sub.2-4O--, and --O(CH.sub.2).sub.1-3O--; [0019]
R.sub.4 is one to three substituents independently selected from
the group consisting of hydrogen; C.sub.1-6alkanyl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; aryl(C.sub.2-6)alkynyl;
C.sub.1-6alkanyloxy; amino; C.sub.1-6alkanylamino;
di(C.sub.1-6alkanyl)amino; C.sub.6-10arylamino wherein
C.sub.6-10aryl is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkoxy, halogen, and hydroxyl;
formylamino; pyridinylamino; C.sub.1-6alkanylcarbonyl;
C.sub.1-6alkanylcarbonyloxy; C.sub.1-6alkanyloxycarbonyl;
aminocarbonyl; C.sub.1-6alkanylaminocarbonyl;
di(C.sub.1-6alkanyl)aminocarbonyl; C.sub.1-6alkanylcarbonylamino;
C.sub.1-6alkanylthio; C.sub.1-6alkanylsulfonyl; halogen; hydroxy;
cyano; hydroxycarbonyl; C.sub.6-10aryl; chromanyl; chromenyl;
furanyl; imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; thienyl; fluoroalkanyl and fluoroalkanyloxy;
or optionally, when R.sub.4 is two substituents attached to
adjacent carbon atoms, the two substituents together form a single
fused moiety; wherein the fused moiety is --(CH.sub.2).sub.3-5--,
--O(CH.sub.2).sub.2-4--, --(CH.sub.2).sub.2-4O--,
--O(CH.sub.2).sub.1-3O--, or --S--C(NH.sub.2).dbd.N--; [0020]
R.sub.5 is one to two substituents independently selected from the
group consisting of hydrogen, C.sub.1-6alkanyl, C.sub.2-6alkenyl,
C.sub.1-6alkanyloxy, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-6alkanylcarbonyl,
C.sub.1-6alkanylcarbonyloxy, C.sub.1-6alkanyloxycarbonyl,
C.sub.1-6alkanylaminocarbonyl, C.sub.1-6alkanylcarbonylamino,
C.sub.1-6alkanylthio, C.sub.1-6alkanylsulfonyl, halogen, hydroxy,
cyano, fluoro(C.sub.1-6)alkanyl and fluoro(C.sub.1-6)alkanyloxy;
[0021] A is --(CH.sub.2).sub.m--, wherein m is 2 or 3; [0022] Y is
O or S; [0023] Z is O, S, NH, N(C.sub.1-6alkanyl), N(OH),
N(OC.sub.1-6alkanyl), or N(phenyl); and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0024] The present invention is also directed to, inter alia,
veterinary and pharmaceutical compositions containing compounds of
Formula (I) wherein the compositions are used to treat mild to
severe pain in warm-blooded animals.
DETAILED DESCRIPTION
[0025] As used herein, the following underlined terms are intended
to have the following meanings:
[0026] "C.sub.a-b" (where a and b are integers) refers to a radical
containing from a to b carbon atoms inclusive. For example,
C.sub.1-3 denotes a radical containing 1, 2 or 3 carbon atoms
[0027] "Alkyl:" refers to a saturated or unsaturated, branched,
straight-chain or cyclic monovalent hydrocarbon radical derived by
the removal of one hydrogen atom from a single carbon atom of a
parent alkane, alkene or alkyne. Typical alkyl groups include, but
are not limited to, methyl; ethyls such as ethanyl, ethenyl,
ethynyl; propyls such as propan-1-yl, propan-2-yl ,
cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl,
cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,
prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,
2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,
but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,
but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,
buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl,
but-3-yn-1-yl, etc.; and the like. Where specific levels of
saturation are intended, the nomenclature "alkanyl", "alkenyl"
and/or "alkynyl" is used, as defined below. In preferred
embodiments, the alkyl groups are (C.sub.1-C.sub.6) alkyl, with
(C.sub.1-C.sub.3) being particularly preferred.
[0028] "Alkanyl:" refers to a saturated branched, straight-chain or
cyclic monovalent hydrocarbon radical derived by the removal of one
hydrogen atom from a single carbon atom of a parent alkane. Typical
alkanyl groups include, but are not limited to, methanyl; ethanyl;
propanyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.;
butyanyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,
2-methyl-propan-2-yl, cyclobutan-1-yl, etc.; and the like. In
preferred embodiments, the alkanyl groups are (C.sub.1-8) alkanyl,
with (C.sub.1-3) being particularly preferred.
[0029] "Alkenyl" refers to an unsaturated branched, straight-chain
or cyclic monovalent hydrocarbon radical having at least one
carbon-carbon double bond derived by the removal of one hydrogen
atom from a single carbon atom of a parent alkene. The radical may
be in either the cis or trans conformation about the double
bond(s). Typical alkenyl groups include, but are not limited to,
ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,
prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;
cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,
2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,
but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,
cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,
etc.; and the like.
[0030] "Alkynyl" refers to an unsaturated branched, straight-chain
or cyclic monovalent hydrocarbon radical having at least one
carbon-carbon triple bond derived by the removal of one hydrogen
atom from a single carbon atom of a parent alkyne. Typical alkynyl
groups include, but are not limited to, ethynyl; propynyls such as
prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as
but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the
like.
[0031] "Heteroalkyl" and Heteroalkanyl" refer to alkyl or alkanyl
radicals, respectively, in which one or more carbon atoms (and any
necessary associated hydrogen atoms) are independently replaced
with the same or different heteroatoms (including any necessary
hydrogen or other atoms). Typical heteroatoms to replace the carbon
atom(s) include, but are not limited to, N, P, O, S, Si, etc.
Preferred heteroatoms are O, N and S. Thus, heteroalkanyl radicals
can contain one or more of the same or different heteroatomic
groups, including, by way of example and not limitation, epoxy
(--O--), epidioxy (--O--O--), thioether (--S--), epidithio
(--SS--), epoxythio (--O--S--), epoxyimino (--O--NR'--), imino
(--NR'--), biimino (--NR'--NR'--), azino (.dbd.N--N.dbd.), azo
(--N.dbd.N--), azoxy (--N--O--N--), azimino (--NR'--N.dbd.N--),
phosphano (--PH--), .lamda..sup.4-sulfano (--SH.sub.2--), sulfonyl
(--S(O).sub.2--), and the like, where each R' is independently
hydrogen or (C.sub.1-C.sub.6) alkyl.
[0032] "Parent Aromatic Ring System:" refers to an unsaturated
cyclic or polycyclic ring system having a conjugated .pi. electron
system. Specifically included within the definition of "parent
aromatic ring system" are fused ring systems in which one or more
rings are aromatic and one or more rings are saturated or
unsaturated, such as, for example, indane, indene, phenalene, etc.
Typical parent aromatic ring systems include, but are not limited
to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, coronene, fluoranthene, fluorene,
hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane,
indene, naphthalene, octacene, octaphene, octalene, ovalene,
penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,
phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,
rubicene, triphenylene, trinaphthalene, and the like
[0033] "Aryl:" refers to a monovalent aromatic hydrocarbon radical
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, radicals derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene, and the like. In preferred embodiments, the aryl
group is (C.sub.5-20) aryl, with (C.sub.5-10) being particularly
preferred. Particularly preferred aryl groups are phenyl and
naphthyl groups.
[0034] "Arylalkyl:" refers to an acyclic alkyl group in which one
of the hydrogen atoms bonded to a carbon atom, typically a terminal
carbon atom, is replaced with an aryl radical. Typical arylalkyl
groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,
2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,
2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and
the like. Where specific alkyl moieties are intended, the
nomenclature arylalkanyl, arylakenyl and/or arylalkynyl is used.
[In preferred embodiments, the arylalkyl group is (C.sub.6-26)
arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-6) and the aryl moiety is (C.sub.5-20).
In particularly preferred embodiments the arylalkyl group is
(C.sub.6-13), e.g., the alkanyl, alkenyl or alkynyl moiety of the
arylalkyl group is (C.sub.1-3) and the aryl moiety is (C.sub.5-10).
Even more preferred arylalkyl groups are phenylalkanyls.
[0035] "Alkanyloxy:" refers to a saturated branched, straight-chain
or cyclic monovalent hydrocarbon alcohol radical derived by the
removal of the hydrogen atom from the hydroxide oxygen of the
alcohol. Typical alkanyloxy groups include, but are not limited to,
methanyloxy; ethanyloxy; propanyloxy groups such as propan-1-yloxy
(CH.sub.3CH.sub.2CH.sub.2O--), propan-2-yloxy
((CH.sub.3).sub.2CHO--), cyclopropan-1-yloxy, etc.; butanyloxy
groups such as butan-1-yloxy, butan-2-yloxy,
2-methyl-propan-1-yloxy, 2-methyl-propan-2-yloxy,
cyclobutan-1-yloxy, etc.; and the like. In preferred embodiments,
the alkanyloxy groups are (C.sub.1-8) alkanyloxy groups, with
(C.sub.1-3) being particularly preferred.
[0036] "Parent Heteroaromatic Ring System:" refers to a parent
aromatic ring system in which one carbon atom is replaced with a
heteroatom. Heteroatoms to replace the carbon atoms include N, O,
and S. Specifically included within the definition of "parent
heteroaromatic ring systems" are fused ring systems in which one or
more rings are aromatic and one or more rings are saturated or
unsaturated, such as, for example, arsindole, chromane, chromene,
indole, indoline, xanthene, etc. Typical parent heteroaromatic ring
systems include, but are not limited to, carbazole, imidazole,
indazole, indole, indoline, indolizine, isoindole, isoindoline,
isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole,
oxazole, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine,
pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,
quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like.
[0037] "Heteroaryl:" refers to a monovalent heteroaromatic radical
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Typical heteroaryl groups
include, but are not limited to, radicals derived from carbazole,
imidazole, indazole, indole, indoline, indolizine, isoindole,
isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,
oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine,
pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,
quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like. In preferred
embodiments, the heteroaryl group is a 5-20 membered heteroaryl,
with 5-10 membered heteroaryl being particularly preferred.
[0038] "Cycloheteroalkyl:" refers to a saturated or unsaturated
monocyclic or bicyclic alkyl radical in which one carbon atom is
replaced with N, O or S. In certain specified embodiments the
cycloheteroalkyl may contain up to four heteroatoms independently
selected from N, O or S. Typical cycloheteroalkyl moieties include,
but are not limited to, radicals derived from imidazolidine,
morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine,
quinuclidine, and the like. In preferred embodiments, the
cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.
[0039] "Cycloheteroalkanyl:" refers to a saturated monocyclic or
bicyclic alkanyl radical in which one carbon atom is replaced with
N, O or S. In certain specified embodiments the cycloheteroalkanyl
may contain up to four heteroatoms independently selected from N, O
or S. Typical cycloheteroalkanyl moieties include, but are not
limited to, radicals derived from imidazolidine, morpholine,
piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine,
and the like. In preferred embodiments, the cycloheteroalkanyl is a
3-6 membered cycloheteroalkanyl.
[0040] "Cycloheteroalkenyl:" refers to a saturated monocyclic or
bicyclic alkenyl radical in which one carbon atom is replaced with
N, O or S. In certain specified embodiments the cycloheteroalkenyl
may contain up to four heteroatoms independently selected from N, O
or S. Typical cycloheteroalkenyl moieties include, but are not
limited to, radicals derived from imidazoline, pyrazoline,
pyrroline, indoline, pyran, and the like. In preferred embodiments,
the cycloheteroalkanyl is a 3-6 membered cycloheteroalkanyl.
[0041] "Substituted:" refers to a radical in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, --X, --R, --O.sup.-, .dbd.O, --OR, --O--OR, --SR,
--S.sup.-, .dbd.S, --NRR, .dbd.NR, --CX.sub.3, --CN, --OCN, --SCN,
--NCO, --NCS, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --NHOH,
--S(O).sub.2O.sup.-, --S(O).sub.2OH, --S(O).sub.2R,
--P(O)(O.sup.-).sub.2, --P(O)(OH).sub.2, --C(O)R, --C(O)X, --C(S)R,
--C(S)X, --C(O)OR, --C(O)O.sup.-, --C(S)OR, --C(O)SR, --C(S)SR,
--C(O)NRR, --C(S)NRR and --C(NR)NRR, where each X is independently
a halogen (preferably --F, --Cl or --Br) and each R is
independently --H, alkyl, alkanyl, alkenyl, alkynyl, alkylidene,
alkylidyne, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl or heteroaryl-heteroalkyl, as defined herein.
Preferred substituents include hydroxy, halogen, C.sub.1-8alkyl,
C.sub.1-8alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,
C.sub.1-8alkylthio, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkanyloxy,
nitro, amino, C.sub.1-8alkylamino, C.sub.1-8dialkylamino,
C.sub.3-8cycloalkylamino, cyano, carboxy,
C.sub.1-7alkanyloxycarbonyl, C.sub.1-7alkylcarbonyloxy, formyl,
carbamoyl, phenyl, aroyl, carbamoyl, amidino,
(C.sub.1-8alkylamino)carbonyl, (arylamino)carbonyl and
aryl(C.sub.1-8alkyl)carbonyl.
[0042] With reference to substituents, the term "independently"
means that when more than one of such substituent is possible, such
substituents may be the same or different from each other.
[0043] Throughout this disclosure, the terminal portion of the
designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenylC.sub.1-6alkanylaminocarbonylC.sub.1-6alkyl" substituent
refers to a group of the formula
##STR00002##
[0044] The present invention is directed, inter alia, to compounds
of Formula (I) and compositions comprising a compound of Formula
(I):
##STR00003##
wherein: [0045] G is --C(Z)N(R.sub.1)R.sub.2, C.sub.6-10aryl, or a
heterocycle selected from the group consisting of imidazolyl,
triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,
imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, furyl, indazolyl, indolyl, indolinyl,
isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl,
quinolinyl, isoquinolinyl, and pyridinyl; wherein aryl and the
heterocycles of G are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, nitro, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio,
C.sub.1-8alkanylsulfonyl, C.sub.1-8alkanylsulfonylamino,
aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,
aminothiocarbonylamino, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; [0046] R.sub.1 is a substituent
selected from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, and C.sub.2-8alkynyl; [0047] R.sub.2 is a
substituent selected from the group consisting of hydrogen;
C.sub.1-8alkanyl; C.sub.2-8alkenyl; C.sub.2-8alkynyl;
C.sub.6-10aryl; and C.sub.1-8cycloalkanyl; wherein C.sub.1-8alkanyl
is optionally substituted with one to three substituents
independently selected from the group consisting of phenyl, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-6alkanyloxy, thioC.sub.1-6alkanyloxy, hydroxy, fluoro,
chloro, cyano, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, C.sub.1-6alkanyloxycarbonyl, and
aryloxy; and wherein any aryl-containing substituents and
C.sub.1-8cycloalkanyl substituents of R.sub.2 are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkanyloxy, trifluoromethyl,
trifluoromethoxy, phenyl, halogen, cyano, hydroxy,
C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl, and
C.sub.1-8alkanylsulfonylamino; [0048] or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, hydroxy(C.sub.1-8)alkanyl, hydroxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino, and halogen;
[0049] R.sub.3 is a substituent selected from the group consisting
of hydrogen, C.sub.1-8alkanyl, halo.sub.1-3(C.sub.1-8)alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkanyl,
cycloalkanyl(C.sub.1-8)alkanyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
C.sub.1-8alkanyloxycarbonyl,
halo.sub.1-3(C.sub.1-8)alkanylcarbonyl, formyl, thioformyl,
carbamimidoyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkenyl,
phenyl(C.sub.1-8)alkynyl, naphthyl(C.sub.1-8)alkanyl and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl,
isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,
quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl,
naphthyl and heteroaryl are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl, C.sub.2-6alkenyl, C.sub.1-6alkanyloxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-6alkanylcarbonyl, C.sub.1-6alkanylcarbonyloxy,
C.sub.1-6alkanylcarbonylamino, C.sub.1-6alkanylthio,
C.sub.1-6alkanylsulfonyl, halogen, hydroxy, cyano,
fluoro(C.sub.1-6)alkanyl, thioureido, and
fluoro(C.sub.1-6)alkanyloxy; alternatively, when phenyl and
heteroaryl are optionally substituted with alkanyl or alkanyloxy
substituents attached to adjacent carbon atoms, the two
substituents can together form a fused cyclic alkanyl or
cycloheteroalkanyl selected from the group consisting of
--(CH.sub.2).sub.3-5--, --O(CH.sub.2).sub.2-4--,
--(CH.sub.2).sub.2-4O--, and --O(CH.sub.2).sub.1-3O--; [0050]
R.sub.4 is one to three substituents independently selected from
the group consisting of hydrogen; C.sub.1-6alkanyl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; aryl(C.sub.2-6)alkynyl;
C.sub.1-6alkanyloxy; amino; C.sub.1-6alkanylamino;
di(C.sub.1-6alkanyl)amino; C.sub.6-10arylamino wherein
C.sub.6-10aryl is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkoxy, halogen, and hydroxyl;
formylamino; pyridinylamino; C.sub.1-6alkanylcarbonyl;
C.sub.1-6alkanylcarbonyloxy; C.sub.1-6alkanyloxycarbonyl;
aminocarbonyl; C.sub.1-6alkanylaminocarbonyl;
di(C.sub.1-6alkanyl)aminocarbonyl; C.sub.1-6alkanylcarbonylamino;
C.sub.1-6alkanylthio; C.sub.1-6alkanylsulfonyl; halogen; hydroxy;
cyano; hydroxycarbonyl; C.sub.6-10aryl; chromanyl; chromenyl;
furanyl; imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; thienyl; fluoroalkanyl and fluoroalkanyloxy;
or optionally, when R.sub.4 is two substituents attached to
adjacent carbon atoms, the two substituents together form a single
fused moiety; wherein the fused moiety is --(CH.sub.2).sub.3-5--,
--O(CH.sub.2).sub.2-4--, --(CH.sub.2).sub.2-4O--,
--O(CH.sub.2).sub.1-3O--, or --S--C(NH.sub.2).dbd.N--; [0051]
R.sub.5 is one to two substituents independently selected from the
group consisting of hydrogen, C.sub.1-6alkanyl, C.sub.2-6alkenyl,
C.sub.1-6alkanyloxy, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-6alkanylcarbonyl,
C.sub.1-6alkanylcarbonyloxy, C.sub.1-6alkanyloxycarbonyl,
C.sub.1-6alkanylaminocarbonyl, C.sub.1-6alkanylcarbonylamino,
C.sub.1-6alkanylthio, C.sub.1-6alkanylsulfonyl, halogen, hydroxy,
cyano, fluoro(C.sub.1-6)alkanyl and fluoro(C.sub.1-6)alkanyloxy;
[0052] A is --(CH.sub.2).sub.m--, wherein m is 2 or 3; [0053] Y is
O or S; [0054] Z is O, S, NH, N(C.sub.1-6alkanyl), N(OH),
N(OC.sub.1-6alkanyl), or N(phenyl); and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0055] An embodiment of the present invention is directed to a
compound of Formula (I) wherein the structure is numbered as
defined herein and the substituents are as defined herein.
##STR00004##
[0056] The present invention is directed, inter alia, to analgesic
and anti-pyretic uses of compositions comprising a compound of
Formula (I):
##STR00005##
wherein: [0057] G is --C(Z)N(R.sub.1)R.sub.2, C.sub.6-10aryl, or a
heterocycle selected from the group consisting of: imidazolyl,
triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,
imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, furyl, indazolyl, indolyl, indolinyl,
isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, benzoxazolyl,
quinolinyl, isoquinolinyl, and pyridinyl; wherein aryl and the
heterocycles of G are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, nitro, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio,
C.sub.1-8alkanylsulfonyl, C.sub.1-8alkanylsulfonylamino,
aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,
aminothiocarbonylamino, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; [0058] R.sub.1 is a substituent
selected from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, and C.sub.2-8alkynyl; [0059] R.sub.2 is a
substituent selected from the group consisting of hydrogen;
C.sub.1-8alkanyl; C.sub.2-8alkenyl; C.sub.2-8alkynyl;
C.sub.6-10aryl; and C.sub.1-8cycloalkanyl; wherein C.sub.1-8alkanyl
is optionally substituted with one to three substituents
independently selected from the group consisting of phenyl, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-6alkanyloxy, thioC.sub.1-6alkanyloxy, hydroxy, fluoro,
chloro, cyano, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, C.sub.1-6alkanyloxycarbonyl, and
aryloxy; and wherein any aryl-containing substituents and
C.sub.1-8cycloalkanyl substituents of R.sub.2 are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, C.sub.2-8alkenyl,
C.sub.2-8alkynyl, C.sub.1-8alkanyloxy, trifluoromethyl,
trifluoromethoxy, phenyl, halogen, cyano, hydroxy,
C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl, and
C.sub.1-8alkanylsulfonylamino; [0060] or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, hydroxy(C.sub.1-8)alkanyl, hydroxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino, and halogen;
[0061] R.sub.3 is a substituent selected from the group consisting
of hydrogen, C.sub.1-8alkanyl, halo.sub.1-3(C.sub.1-8)alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl, C.sub.3-8cycloalkanyl,
cycloalkanyl(C.sub.1-8)alkanyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
C.sub.1-8alkanyloxycarbonyl,
halo.sub.1-3(C.sub.1-8)alkanylcarbonyl, formyl, thioformyl,
carbamimidoyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkenyl,
phenyl(C.sub.1-8)alkynyl, naphthyl(C.sub.1-8)alkanyl and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, indazolyl, indolyl, indolinyl,
isoindolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,
quinolinyl, isoquinolinyl, tetrazolyl, thiazolyl; wherein phenyl,
naphthyl and heteroaryl are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkanyl, C.sub.2-6alkenyl, C.sub.1-6alkanyloxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-6alkanylcarbonyl, C.sub.1-6alkanylcarbonyloxy,
C.sub.1-6alkanylcarbonylamino, C.sub.1-6alkanylthio,
C.sub.1-6alkanylsulfonyl, halogen, hydroxy, cyano,
fluoro(C.sub.1-6)alkanyl, thioureido, and
fluoro(C.sub.1-6)alkanyloxy; alternatively, when phenyl and
heteroaryl are optionally substituted with alkanyl or alkanyloxy
substituents attached to adjacent carbon atoms, the two
substituents can together form a fused cyclic alkanyl or
cycloheteroalkanyl selected from the group consisting of
--(CH.sub.2).sub.3-5--, --O(CH.sub.2).sub.2-4--,
--(CH.sub.2).sub.2-4O--, and --O(CH.sub.2).sub.1-3O--; [0062]
R.sub.4 is one to three substituents independently selected from
the group consisting of hydrogen; C.sub.1-6alkanyl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; aryl(C.sub.2-6)alkynyl;
C.sub.1-6alkanyloxy; amino; C.sub.1-6alkanylamino;
di(C.sub.1-6alkanyl)amino; C.sub.6-10arylamino wherein
C.sub.6-10aryl is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkoxy, halogen, and hydroxy;
formylamino; pyridinylamino; C.sub.1-6alkanylcarbonyl;
C.sub.1-6alkanylcarbonyloxy; C.sub.1-6alkanyloxycarbonyl;
aminocarbonyl; C.sub.1-6alkanylaminocarbonyl;
di(C.sub.1-6alkanyl)aminocarbonyl; C.sub.1-6alkanylcarbonylamino;
C.sub.1-6alkanylthio; C.sub.1-6alkanylsulfonyl; halogen; hydroxy;
cyano; hydroxycarbonyl; C.sub.6-10aryl; chromanyl; chromenyl;
furanyl; imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; thienyl; fluoroalkanyl and fluoroalkanyloxy;
or optionally; when R.sub.4 is two substituents attached to
adjacent carbon atoms; the two substituents together form a single
fused moiety; wherein the fused moiety is --(CH.sub.2).sub.3-5--,
--O(CH.sub.2).sub.2-4--, --(CH.sub.2).sub.2-4O--,
--O(CH.sub.2).sub.1-3O--, or --S--C(NH.sub.2).dbd.N--; [0063]
R.sub.5 is one to two substituents independently selected from the
group consisting of hydrogen, C.sub.1-6alkanyl, C.sub.2-6alkenyl,
C.sub.1-6alkanyloxy, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-6alkanylcarbonyl,
C.sub.1-6alkanylcarbonyloxy, C.sub.1-6alkanyloxycarbonyl,
C.sub.1-6alkanylaminocarbonyl, C.sub.1-6alkanylcarbonylamino,
C.sub.1-6alkanylthio, C.sub.1-6alkanylsulfonyl, halogen, hydroxy,
cyano, fluoro(C.sub.1-6)alkanyl and fluoro(C.sub.1-6)alkanyloxy;
[0064] A is --(CH.sub.2).sub.m--, wherein m is 2 or 3; [0065] Y is
O or S; [0066] Z is O, S, NH, N(C.sub.1-6alkanyl), N(OH),
N(OC.sub.1-6alkanyl), or N(phenyl); and enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0067] Embodiments of the present invention include compounds of
Formula (I) wherein, preferably: [0068] a) G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, imidazolinyl, tetrahydropyrimidinyl,
thienyl, pyrazolyl, pyrimidinyl, triazinyl, isothiazolyl,
isoxazolyl, oxazolyl, isoxadiazolyl, and pyridinyl; wherein phenyl
and the heterocycles of G are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
hydroxy(C.sub.1-8)alkanyl, carboxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylcarbonylamino, halogen, hydroxy, cyano, oxo,
thioxo, amino, C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-8alkanylthio, aminocarbonyl, aminothiocarbonyl,
C.sub.1-8alkanylaminocarbonyl, di(C.sub.1-8alkanyl)aminocarbonyl,
and C.sub.1-6alkanyloxycarbonylamino; [0069] b) G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, imidazolinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G (described herein) are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-4alkanyl, C.sub.1-4alkanyloxy,
hydroxy(C.sub.1-4)alkanyl, carboxy(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-8alkanylthio, aminocarbonyl, aminothiocarbonyl,
C.sub.1-8alkanylaminocarbonyl, and
di(C.sub.1-8alkanyl)aminocarbonyl; [0070] c) G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of imidazolyl, tetrazolyl, oxadiazolyl,
thiadiazolyl, oxathiadiazolyl, thienyl, isothiazolyl, isoxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G (described herein) are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-4alkanyl, C.sub.1-4alkanyloxy,
hydroxy(C.sub.1-4)alkanyl, C.sub.1-4alkanylcarbonylamino, hydroxy,
cyano, oxo, thioxo, and aminocarbonyl; [0071] d) R.sub.1 is a
substituent selected from the group consisting of hydrogen and
C.sub.1-4alkanyl; [0072] e) R.sub.1 is selected from the group
consisting of hydrogen, methyl, ethyl, and propyl; [0073] f)
R.sub.1 is selected from the group consisting of hydrogen, methyl,
or ethyl; [0074] g) R.sub.2 is selected from the group consisting
of hydrogen; C.sub.1-4alkanyl; phenyl; and C.sub.1-6cycloalkanyl;
wherein C.sub.1-4alkanyl is optionally substituted with one to
three substituents independently selected from the group consisting
of phenyl, amino, C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino,
C.sub.1-4alkanyloxy, hydroxy, fluoro, chloro, cyano, aminocarbonyl,
C.sub.1-8alkanylaminocarbonyl, di(C.sub.1-8alkanyl)aminocarbonyl,
and phenoxy; and wherein any phenyl-containing substituents and
C.sub.1-6cycloalkanyl substituents of R.sub.2 are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl, C.sub.1-8alkanyloxy,
trifluoromethyl, phenyl, fluoro, hydroxy, C.sub.1-8alkanylthio,
C.sub.1-8alkanylsulfonyl, and C.sub.1-8alkanylsulfonylamino; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a 5-7 membered cycloheteroalkyl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-4alkanyl,
hydroxy(C.sub.1-4)alkanyl, hydroxy, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, and fluoro; [0075] h) R.sub.2 is
selected from the group consisting of hydrogen, C.sub.1-4alkanyl,
phenyl, and C.sub.1-6cycloalkanyl, wherein C.sub.1-4alkanyl is
optionally substituted with one to three substituents independently
selected from the group consisting of phenyl, C.sub.1-4alkanyloxy,
hydroxy, fluoro, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and phenoxy; and wherein any
phenyl-containing substituent of R.sub.2 is optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro,
hydroxy, and C.sub.1-6alkanylthio; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkanyl and hydroxy; [0076] i) R.sub.2 is selected from
the group consisting of hydrogen, C.sub.1-4alkanyl and phenyl,
wherein C.sub.1-4alkanyl is optionally substituted with one to
three substituents independently selected from the group consisting
of phenyl, C.sub.1-4alkanyloxy, hydroxy, fluoro, and phenoxy; and
wherein any phenyl-containing substituent of R.sub.2 is optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl, C.sub.1-6alkanyloxy,
fluoro, and hydroxy; or R.sub.1 and R.sub.2 taken together with the
nitrogen to which they are attached form a pyrrolidinyl or
piperidinyl ring wherein said pyrrolidinyl or piperidinyl is
optionally substituted with a substituent selected from the group
consisting of C.sub.1-3alkanyl and hydroxy; [0077] j) R.sub.3 is
selected from the group consisting of hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
thioformyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, and heteroaryl(C.sub.1-8)alkanyl wherein
heteroaryl is selected from the group consisting of
benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,
indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,
tetrazolyl; wherein phenyl and heteroaryl are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyloxy and hydroxy; or
optionally, when phenyl and heteroaryl are optionally substituted
with two substituents attached to adjacent carbon atoms, the two
substituents together form a single fused moiety; wherein the
moiety is selected from --O(CH.sub.2).sub.1-3O--; [0078] k) R.sub.3
is selected from the group consisting of hydrogen, methyl, allyl,
2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,
methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,
isoquinolinyl, tetrazolyl; wherein the phenyl in any
phenyl-containing substituent is optionally substituted with one
hydroxyl group; [0079] l) R.sub.3 is hydrogen, methyl, allyl, or
heteroarylmethyl wherein heteroaryl is selected from the group
consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl,
and thienyl; [0080] m) R.sub.4 is one to three substituents
independently selected from the group consisting of hydrogen;
C.sub.1-6alkanyl; C.sub.1-6alkanyloxy; C.sub.6-10arylamino wherein
C.sub.6-10aryl is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl; C.sub.1-6alkoxy, halogen, and hydroxy;
formylamino; pyridinylamino; aminocarbonyl;
C.sub.1-6alkanylaminocarbonyl; C.sub.1-6alkanylcarbonylamino;
halogen; hydroxy; C.sub.6-10aryl; chromanyl; chromenyl; furanyl;
imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; and thienyl; [0081] n) R.sub.4 is one to two
substituents independently selected from the group consisting of
hydrogen, C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, halogen, phenyl,
furanyl, imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy; [0082] o)
R.sub.4 is one to two substituents independently selected from the
group consisting of hydrogen, methyl, methoxy, bromo, fluoro,
.alpha.'- or .beta.'-phenyl, .alpha.'- or .beta.'-pyridinyl,
.alpha.'- or .beta.'-furanyl, and hydroxy; [0083] p) R.sub.5 is one
to two substituents independently selected from the group
consisting of hydrogen and halogen; [0084] q) R.sub.5 is hydrogen;
[0085] r) A is --(CH.sub.2).sub.2-3--; [0086] s) A is
--(CH.sub.2).sub.2--; [0087] t) Y is O or S; [0088] u) Z is O, NH,
N(C.sub.1-6alkanyl), N(OH), N(OC.sub.1-6alkanyl), or N(phenyl);
[0089] v) Z is O, NH, or N(OH); [0090] w) Z is O or NH; [0091] aa)
G is --C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected
from the group consisting of tetrazolyl, oxadizolyl, furyl,
quinolinyl, thienyl, and pyridinyl; wherein phenyl and the
heterocycles of G are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; [0092] bb) G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadizolyl, furyl, quinolinyl,
thienyl, and pyridinyl; wherein phenyl and the heterocycles of G
are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, hydroxy(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, and
aminocarbonyl; [0093] cc) G is --C(Z)N(R.sub.1)R.sub.2; tetrazolyl;
pyridinyl; oxadiazolyl optionally substituted with oxo; or phenyl
optionally substituted with (C.sub.1-8)alkanylcarbonylamino; [0094]
dd) G is --C(Z)N(R.sub.1)R.sub.2, 1H-tetrazol-4-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 2-methylcarbonylaminophenyl,
pyridin-3-yl or pyridin-4-yl; [0095] dd) R.sub.2 is selected from
the group consisting of hydrogen and C.sub.1-4alkanyl; wherein
C.sub.1-4alkanyl is optionally substituted with phenyl; or R.sub.1
and R.sub.2 taken together with the nitrogen to which they are
attached form a pyrrolidinyl wherein said pyrrolidinyl is
optionally substituted with hydroxy; [0096] ee) R.sub.2 is selected
from the group consisting of hydrogen, methyl, ethyl, and
phenethyl; or R.sub.1 and R.sub.2 taken together with the nitrogen
to which they are attached form pyrrolidin-1-yl,
3-hydoxypyrrolidin-1-yl or 3-(S)-hydoxypyrrolidin-1-yl; [0097] ff)
R.sub.3 is selected from the group consisting of hydrogen,
C.sub.1-8alkanyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
thioformyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, and heteroaryl(C.sub.1-8)alkanyl wherein
heteroaryl is selected from the group consisting of
benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,
indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, thiazolyl,
isoquinolinyl, tetrazolyl; wherein phenyl and heteroaryl are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyloxy and
hydroxy; or optionally, when phenyl and heteroaryl are optionally
substituted with two substituents attached to adjacent carbon
atoms, the two substituents together form a single fused moiety;
wherein the moiety is selected from --O(CH.sub.2).sub.1-3O--;
[0098] gg) R.sub.3 is selected from the group consisting of
hydrogen, methyl, methylbutenyl, propenyl, benzyl, phenethyl, and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of imidazolyl, furanyl, pyridinyl,
thienyl, and thiazolyl; [0099] hh) R.sub.3 is selected from the
group consisting of hydrogen, methyl, 3-methyl-2-butenyl,
2-propenyl, benzyl, 2-phenethyl, pyridin-2-ylmethyl,
fur-3-ylmethyl, thiophene-2-ylmethyl, 1H-imidazol-2-ylmethyl, and
thiazol-2-ylmethyl; [0100] ii) R.sub.4 is one to two substituents
independently selected from the group consisting of hydrogen,
methyl, phenyl, bromo, fluoro, aminocarbonyl, chloro and hydroxy;
[0101] jj) R.sub.4 is one to two substituents independently
selected from the group consisting of hydrogen, .alpha.'-hydroxy
and .alpha.'-methoxy; [0102] kk) R.sub.4 is unsubstituted or
substituted at the .alpha.' position; [0103] ll) R.sub.4 is
hydrogen and Y is O; [0104] mm) R.sub.4 is .alpha.'-hydroxy and Y
is O; [0105] nn) R.sub.4 is hydrogen and Y is S; [0106] oo) R.sub.4
is .alpha.'-hydroxy and Y is S; and combinations of a) through oo)
above.
[0107] One embodiment of the present invention is a compound of
Formula (I) wherein: [0108] G is --C(Z)N(R.sub.1)R.sub.2, phenyl,
or a heterocycle selected from the group consisting of imidazolyl,
triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,
imidazolinyl, tetrahydropyrimidinyl, thienyl, pyrazolyl,
pyrimidinyl, triazinyl, isothiazolyl, isoxazolyl, oxazolyl,
isoxadiazolyl, and pyridinyl; wherein phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; [0109] R.sub.1 is hydrogen or
C.sub.1-4alkanyl; [0110] R.sub.2 is selected from the group
consisting of hydrogen; C.sub.1-4alkanyl; phenyl; and
C.sub.1-6cycloalkanyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-4alkanyloxy, hydroxy, fluoro,
chloro, cyano, aminocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and phenoxy; and wherein the
phenyl and C.sub.1-6cycloalkanyl substituents of R.sub.2 are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-8alkanyl,
C.sub.1-8alkanyloxy, trifluoromethyl, phenyl, fluoro, hydroxy,
C.sub.1-8alkanylthio, C.sub.1-8alkanylsulfonyl, and
C.sub.1-8alkanylsulfonylamino; or R.sub.1 and R.sub.2 taken
together with the nitrogen to which they are attached form a 5-7
membered cycloheteroalkyl optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkanyl, hydroxy(C.sub.1-4)alkanyl, hydroxy, amino,
C.sub.1-6alkanylamino, di(C.sub.1-6alkanyl)amino, and fluoro;
[0111] R.sub.3 is selected from the group consisting of hydrogen,
C.sub.1-8alkanyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
thioformyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, and heteroaryl(C.sub.1-8)alkanyl wherein
heteroaryl is selected from the group consisting of
benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl, thienyl,
indolyl, indolinyl, isoquinolinyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolyl, quinolinyl, isoquinolinyl,
tetrazolyl; wherein phenyl and heteroaryl are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyloxy and hydroxy; or
optionally, when phenyl and heteroaryl are optionally substituted
with two substituents attached to adjacent carbon atoms, the two
substituents together form a single fused moiety; wherein the
moiety is selected from --O(CH.sub.2).sub.1-3O--; [0112] R.sub.4 is
one to three substituents independently selected from the group
consisting of hydrogen; C.sub.1-6alkanyl; C.sub.1-6alkanyloxy;
C.sub.6-10arylamino wherein C.sub.6-10aryl is optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkanyl; C.sub.1-6alkoxy,
halogen, and hydroxy; formylamino; pyridinylamino; aminocarbonyl;
C.sub.1-6alkanylaminocarbonyl; C.sub.1-6alkanylcarbonylamino;
halogen; hydroxy; C.sub.6-10aryl; chromanyl; chromenyl; furanyl;
imidazolyl; indazolyl; indolyl; indolinyl; isoindolinyl;
isoquinolinyl; isothiazolyl; isoxazolyl; naphthyridinyl; oxazolyl;
pyrazinyl; pyrazolyl; pyridazinyl; pyridinyl; pyrimidinyl;
pyrrolyl; quinazolinyl; quinolinyl; quinolizinyl; quinoxalinyl;
tetrazolyl; thiazolyl; and thienyl; [0113] R.sub.5 is one to two
substituents independently selected from the group consisting of
hydrogen and halogen; [0114] A is CH.sub.2CH.sub.2; [0115] Y is O
or S; [0116] Z is O, NH, N(C.sub.1-6alkanyl), N(OH),
N(OC.sub.1-6alkanyl), or N(phenyl); and [0117] enantiomers,
diastereomers, tautomers, solvates, and pharmaceutically acceptable
salts thereof.
[0118] Another embodiment of the present invention is a compound of
Formula (I) wherein: [0119] G is --C(Z)N(R.sub.1)R.sub.2, phenyl,
or a heterocycle selected from the group consisting of imidazolyl,
tetrazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl,
imidazolinyl, thienyl, pyrazolyl, pyrimidinyl, triazinyl,
isothiazolyl, isoxazolyl, oxazolyl, isoxadiazolyl, and pyridinyl;
wherein phenyl and the heterocycles of G (described herein) are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-4alkanyl,
C.sub.1-4alkanyloxy, hydroxy(C.sub.1-4)alkanyl,
carboxy(C.sub.1-4)alkanyl, C.sub.1-4alkanylcarbonylamino, hydroxy,
cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl, and
di(C.sub.1-8alkanyl)aminocarbonyl; [0120] R.sub.1 is selected from
the group consisting of hydrogen, methyl, ethyl, and propyl; [0121]
R.sub.2 is selected from the group consisting of hydrogen,
C.sub.1-4alkanyl, phenyl, and C.sub.1-6cycloalkanyl; wherein
C.sub.1-4alkanyl is optionally substituted with one to three
substituents independently selected from the group consisting of
phenyl, C.sub.1-4alkanyloxy, hydroxy, fluoro, aminocarbonyl,
C.sub.1-8alkanylaminocarbonyl, di(C.sub.1-8alkanyl)aminocarbonyl,
and phenoxy; and wherein any phenyl-containing substituent of
R.sub.2 is optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, hydroxy, and
C.sub.1-6alkanylthio; or R.sub.1 and R.sub.2 taken together with
the nitrogen to which they are attached form a pyrrolidinyl or
piperidinyl ring wherein said pyrrolidinyl or piperidinyl is
optionally substituted with a substituent selected from the group
consisting of C.sub.1-3alkanyl and hydroxy; [0122] R.sub.3 is
selected from the group consisting of hydrogen, methyl, allyl,
2-methyl-allyl, propynyl, hydroxyethyl, methylthioethyl,
methoxyethyl, thioformyl, phenyliminomethyl, phenethyl, and
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, thienyl, pyrimidinyl, pyrrolyl, quinolinyl,
isoquinolinyl, tetrazolyl wherein the phenyl in any
phenyl-containing substituent is optionally substituted with one
hydroxyl group; [0123] R.sub.4 is one to two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, halogen, phenyl, furanyl,
imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy; [0124]
R.sub.5 is hydrogen; [0125] A is CH.sub.2CH.sub.2; [0126] Y is O or
S; [0127] Z is O, NH, or N(OH); and [0128] enantiomers,
diastereomers, tautomers, solvates, and pharmaceutically acceptable
salts thereof.
[0129] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein: [0130] G
is selected from --C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle
selected from the group consisting of imidazolyl, tetrazolyl,
oxadiazolyl, thiadiazolyl, oxathiadiazolyl, thienyl, isothiazolyl,
isoxazolyl, isoxadiazolyl, and pyridinyl; wherein phenyl and the
heterocycles of G are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, hydroxy(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, and
aminocarbonyl; [0131] R.sub.1 is hydrogen, methyl, or ethyl; [0132]
R.sub.2 is independently selected from the group consisting of
hydrogen, C.sub.1-4alkanyl and phenyl; wherein C.sub.1-4alkanyl is
optionally substituted with one to three substituents independently
selected from the group consisting of phenyl, C.sub.1-4alkanyloxy,
hydroxy, fluoro, and phenoxy; and wherein any phenyl-containing
substituent of R.sub.2 is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a pyrrolidinyl or piperidinyl ring wherein said
pyrrolidinyl or piperidinyl are optionally substituted with a
substituent selected from the group consisting of C.sub.1-3alkanyl
and hydroxy; [0133] R.sub.3 is hydrogen, methyl, allyl, or
heteroarylmethyl wherein heteroaryl is selected from the group
consisting of benzo[1,3]dioxolyl, imidazolyl, furanyl, pyridinyl,
and thienyl; [0134] R.sub.4 is one to two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, halogen, phenyl, furanyl,
imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy; [0135] A
is CH.sub.2CH.sub.2; [0136] Y is O or S; [0137] Z is O or NH; and
[0138] enantiomers, diasteromers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0139] Another embodiment of the present invention is directed to
compounds of Formula (I) wherein: [0140] G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadiazolyl, furyl, quinolinyl,
thienyl, and pyridinyl; wherein phenyl and the heterocycles of G
are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-8alkanyl, C.sub.1-8alkanyloxy, hydroxy(C.sub.1-8)alkanyl,
carboxy(C.sub.1-8)alkanyl, C.sub.1-8alkanylcarbonylamino, halogen,
hydroxy, cyano, oxo, thioxo, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, C.sub.1-8alkanylthio, aminocarbonyl,
aminothiocarbonyl, C.sub.1-8alkanylaminocarbonyl,
di(C.sub.1-8alkanyl)aminocarbonyl, and
C.sub.1-6alkanyloxycarbonylamino; [0141] R.sub.1 is C.sub.1-4
alkanyl, or hydrogen; [0142] R.sub.2 is hydrogen or C.sub.1-4
alkanyl optionally substituted with phenyl; [0143] or R.sub.1 and
R.sub.2 taken together with the nitrogen to which they are attached
form a pyrrolidinyl ring optionally substituted with hydroxy;
[0144] Z is NH or oxygen; [0145] R.sub.3 is
pyridinyl(C.sub.1-8)alkanyl, furyl(C.sub.1-8)alkanyl, C.sub.1-5
alkanyl, hydrogen, C.sub.2-8 alkenyl, thienyl(C.sub.1-8)alkanyl,
imidazolyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkanyl, or
thiazolyl(C.sub.1-8)alkanyl; [0146] R.sub.4 is hydrogen, C.sub.1-6
alkanyl, C.sub.1-6 alkanyloxy, hydroxy, halogen, aminocarbonyl, or
phenyl; [0147] R.sub.5 is hydrogen; [0148] A is CH.sub.2CH.sub.2;
[0149] Y is O or S; [0150] Z is O or NH; and [0151] enantiomers,
diastereomers, tautomers, solvates, and pharmaceutically acceptable
salts thereof.
[0152] Another embodiment of the present invention is directed to
compounds of Formula (I) wherein: [0153] G is
--C(Z)N(R.sub.1)R.sub.2; tetrazolyl, oxadiazolyl optionally
substituted with oxo; phenyl optionally substituted with
(C.sub.1-8)alkanylcarbonylamino; or pyridinyl; [0154] R.sub.1 is
C.sub.1-4 alkanyl, or hydrogen; [0155] R.sub.2 is hydrogen or
C.sub.1-4 alkanyl optionally substituted with phenyl; [0156] or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a pyrrolidinyl ring optionally substituted with
hydroxy; [0157] Z is NH or oxygen; [0158] R.sub.3 is
pyridinyl(C.sub.1-8)alkanyl, furyl(C.sub.1-8)alkanyl, C.sub.1-5
alkanyl, hydrogen, C.sub.2-8 alkenyl, thienyl(C.sub.1-8)alkanyl,
imidazolyl(C.sub.1-8)alkanyl, phenyl(C.sub.1-8)alkanyl, or
thiazolyl(C.sub.1-8)alkanyl; [0159] R.sub.4 is hydrogen,
.alpha.'-hydroxy, or .alpha.'-methoxy; [0160] R.sub.5 is hydrogen;
[0161] A is CH.sub.2CH.sub.2; [0162] Y is O or S; [0163] Z is O or
NH; and [0164] enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0165] Another embodiment of the present invention is directed to
compounds of Formula (I) wherein: [0166] G is
--C(Z)N(R.sub.1)R.sub.2, 1H-tetrazol-4-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 2-methylcarbonylaminophenyl,
3-furyl, quinolin-3-yl, thiophen-3-yl, pyridin-3-yl or
pyridin-4-yl, [0167] R.sub.1 is hydrogen, ethyl, or methyl, [0168]
R.sub.2 is methyl, ethyl, phenethyl, or hydrogen; [0169] or R.sub.1
and R.sub.2 taken together with the nitrogen to which they are
attached form pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, or
3-(S)-hydroxypyrrolidin-1-yl; [0170] Z is NH or oxygen, [0171]
R.sub.3 is pyridin-2-ylmethyl, fur-3-ylmethyl, methyl, hydrogen,
3-methyl-2-butenyl, thiophene-2-ylmethyl, 2-propenyl,
1H-imidazol-2-ylmethyl, 2-phenethyl, thiazol-2-ylmethyl, benzyl, or
allyl; [0172] R.sub.4 is hydrogen, .alpha.'-methyl,
.alpha.'-phenyl, .beta.''-bromo, .beta.''-fluoro,
.alpha.'-aminocarbonyl, .alpha.'-chloro, .alpha.'-methoxy; or
.alpha.'-hydroxy; [0173] R.sub.5 is hydrogen; [0174] A is
CH.sub.2CH.sub.2; [0175] Y is O or S; [0176] Z is O or NH; and
[0177] enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0178] Another embodiment of the present invention is directed to
compounds of Formula (I) wherein: [0179] G is
--C(Z)N(R.sub.1)R.sub.2, 1H-tetrazol-4-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl, 2-methylcarbonylaminophenyl,
pyridin-3-yl or pyridin-4-yl; [0180] R.sub.1 is hydrogen, ethyl, or
methyl; [0181] R.sub.2 is methyl, ethyl, phenethyl, or hydrogen;
[0182] or R.sub.1 and R.sub.2 taken together with the nitrogen to
which they are attached form pyrrolidin-1-yl,
3-hydroxypyrrolidin-1-yl, or 3-(S)-hydroxypyrrolidin-1-yl; [0183] Z
is NH or oxygen; [0184] R.sub.3 is pyridin-2-ylmethyl,
fur-3-ylmethyl, methyl, hydrogen, 3-methyl-2-butenyl,
thiophene-2-ylmethyl, 2-propenyl, 1H-imidazol-2-ylmethyl,
2-phenethyl, thiazol-2-ylmethyl, or benzyl; [0185] R.sub.4 is
hydrogen, .alpha.'-hydroxy, or .alpha.'-methoxy; [0186] R.sub.5 is
hydrogen; [0187] A is CH.sub.2CH.sub.2; [0188] Y is O or S; [0189]
Z is O or NH; and [0190] enantiomers, diastereomers, tautomers,
solvates, and pharmaceutically acceptable salts thereof.
[0191] In certain embodiments of Formula (I) when R.sub.1 and
R.sub.2 are taken together with the nitrogen to which they are
attached to form a 5-7 membered cycloheteroalkyl optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-8alkanyl,
hydroxy(C.sub.1-8)alkyanyl, hydroxy, amino, C.sub.1-6alkanylamino,
di(C.sub.1-6alkanyl)amino, and halogen; Z is oxygen.
[0192] In certain embodiments of Formula (I) when R.sub.1 and
R.sub.2 are taken together with the nitrogen to which they are
attached to form a pyrrolidinyl ring optionally substituted with
hydroxy, Z is oxygen.
[0193] Another embodiment of the present invention is a compound of
Formula (I) wherein: [0194] G is selected from
--C(Z)N(R.sub.1)R.sub.2, 2-methylcarbonylaminophenyl,
2-aminocarbonyl-phenyl, 1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,
4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl,
or pyridin-3-yl; [0195] R.sub.1 is hydrogen, methyl, or ethyl;
[0196] R.sub.2 is selected from the group consisting of hydrogen,
C.sub.1-4alkanyl and phenyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, C.sub.1-4alkanyloxy, hydroxy,
fluoro, and phenoxy; and wherein any phenyl-containing substituent
of R.sub.2 is optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy; [0197]
or R.sub.1 and R.sub.2 taken together with the nitrogen to which
they are attached form a pyrrolidinyl or piperidinyl ring; [0198]
R.sub.3 is selected from the group consisting of hydrogen,
C.sub.1-8alkanyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkanyloxy(C.sub.1-8)alkanyl,
C.sub.1-8alkanylthio(C.sub.1-8)alkanyl, hydroxyC.sub.1-8alkanyl,
thioformyl, phenylimino(C.sub.1-8)alkanyl,
phenyl(C.sub.1-8)alkanyl, and heteroaryl(C.sub.1-8)alkanyl wherein
heteroaryl is selected from the group consisting of hydrogen,
methyl, allyl, or heteroarylmethyl; wherein heteroaryl is selected
from the group consisting of benzo[1,3]dioxolyl, imidazolyl,
furanyl, pyridinyl, and thienyl; wherein phenyl and heteroaryl are
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkanyloxy and
hydroxy; or optionally, when phenyl and heteroaryl are optionally
substituted with two substituents attached to adjacent carbon
atoms, the two substituents together form a single fused moiety;
wherein the moiety is selected from --O(CH.sub.2).sub.1-3O--;
[0199] R.sub.4 is one to three substituents independently selected
from the group consisting of hydrogen, C.sub.1-4alkanyl,
C.sub.1-4alkanyloxy, halogen, phenyl, furanyl, imidazolyl,
indazolyl, indolyl, indolinyl, isoindolinyl, isoquinolinyl,
isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl,
tetrazolyl, thiazolyl, thienyl, and hydroxy; [0200] R.sub.5 is
hydrogen; [0201] A is CH.sub.2CH.sub.2; [0202] Y is O or S; [0203]
Z is O or NH; and enantiomers, diastereomers, tautomers, solvates,
and pharmaceutically acceptable salts thereof.
[0204] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein G is
independently selected from --C(Z)N(R.sub.1)R.sub.2,
2-methylcarbonylaminophenyl, 2-aminocarbonyl-phenyl,
1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,
4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl,
and pyridin-3-yl; R.sub.1 is hydrogen, methyl, or ethyl; R.sub.2 is
a substituent selected from the group consisting of hydrogen,
C.sub.1-4alkanyl and phenyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, C.sub.1-4alkanyloxy, hydroxy,
and 2,6-dimethyl-phenoxy; and wherein the any phenyl-containing
substituent of R.sub.2 is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a pyrrolidinyl or piperidinyl ring wherein said
pyrrolidinyl or piperidinyl is optionally substituted with a
substituent selected from the group consisting of C.sub.1-3alkanyl
and hydroxy; R.sub.3 is a substituent selected from the group
consisting of benzo[1,3]dioxol-5-ylmethyl, carbamimidoyl,
1-H-imidazol-4-ylmethyl, phenyliminomethyl, 1-prop-2-ynyl,
thioformyl, 2-hydroxyphenyl-methyl, hydroxy-ethyl, methoxy-ethyl,
2-methyl-allyl, 2-methyl-but-2-enyl, allyl, furan-3-ylmethyl, H,
Me, methylthioethyl, phenethyl, pyridin-2-yl methyl, and
thiophen-2-ylmethyl; R.sub.4 is one to two substituents
independently selected from the group consisting of hydrogen,
C.sub.1-4alkanyl, C.sub.1-4alkanyloxy, halogen, phenyl, furanyl,
imidazolyl, indazolyl, indolyl, indolinyl, isoindolinyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinolinyl, tetrazolyl, thiazolyl, thienyl, and hydroxy; R.sub.5 is
H; A is CH.sub.2CH.sub.2; Y is O or S; and Z is O or NH.
[0205] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein G is
selected from --C(Z)N(R.sub.1)R.sub.2, 2-methylcarbonylaminophenyl,
2-aminocarbonyl-phenyl, 1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,
4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl,
or pyridin-3-yl; R.sub.1 is hydrogen, methyl, or ethyl; R.sub.2 is
a substituent selected from the group consisting of hydrogen,
C.sub.1-4alkanyl and phenyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, methoxy, hydroxy, and
2,6-dimethyl-phenoxy; and wherein any phenyl-containing substituent
of R.sub.2 is optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy; or
R.sub.1 and R.sub.2 taken together with the nitrogen to which they
are attached form a pyrrolidinyl or piperidinyl ring wherein said
pyrrolidinyl or piperidinyl are optionally substituted with a
substituent selected from the group consisting of C.sub.1-3alkanyl
and hydroxy; R.sub.3 is a substituent selected from the group
consisting of benzo[1,3]dioxol-5-ylmethyl, carbamimidoyl,
1-H-imidazol-4-yl methyl, phenyliminomethyl, 1-prop-2-ynyl,
thioformyl, 2-hydroxyphenyl-methyl, hydroxyethyl, methoxyethyl,
allyl, furan-3-yl methyl, H, Me, methylthioethyl, and phenethyl;
R.sub.4 is one to two substituents independently selected from the
group consisting of hydrogen, methyl, methoxy, bromo, fluoro,
.alpha.'- or .beta.'-phenyl, .alpha.'- or .beta.'-pyridinyl,
.alpha.'- or .beta.'-furanyl, and hydroxy; R.sub.5 is H; A is
CH.sub.2CH.sub.2; Y is O or S; and Z is O or NH.
[0206] Another embodiment of the present invention is directed to
compositions comprising a compound of Formula (I) wherein G is
selected from --C(Z)N(R.sub.1)R.sub.2, 2-methylcarbonylaminophenyl,
2-aminocarbonyl-phenyl, 1H-tetrazol-4-yl, 2-methyl-tetrazol-5-yl,
4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
4H-[1,2,4]-oxadiazol-5-thioxo-3-yl,
4H-[1,2,4]thiadiazol-5-oxo-3-yl, [1,2,3,5]oxathiadiazol-2-oxo-4-yl,
or pyridin-3-yl; R.sub.1 is hydrogen, methyl, or ethyl; R.sub.2 is
a substituent selected from the group consisting of hydrogen,
C.sub.1-4alkanyl and phenyl; wherein C.sub.1-4alkanyl is optionally
substituted with one to three substituents independently selected
from the group consisting of phenyl, methoxy, hydroxy, and
2,6-dimethyl-phenoxy; and wherein any phenyl-containing substituent
of R.sub.2 is optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-6alkanyl, C.sub.1-6alkanyloxy, fluoro, and hydroxy;
alternatively R.sub.1 and R.sub.2 are taken together with the
nitrogen to which they are attached to form a pyrrolidinyl or
piperidinyl ring wherein said pyrrolidinyl or piperidinyl are
optionally substituted with a substituent selected from the group
consisting of C.sub.1-3alkanyl and hydroxy; R.sub.3 is a
substituent selected from the group consisting of H,
benzo[1,3]dioxol-5-ylmethyl, 1-H-imidazol-4-yl methyl,
furan-3-ylmethyl, pyridin-2-ylmethyl, and phenyliminomethyl;
R.sub.4 is a substituent independently selected from the group
consisting of hydrogen, methyl, methoxy, bromo, fluoro .alpha.'- or
.beta.'-phenyl, .alpha.'- or .beta.'-pyridinyl, .alpha.'- or
.beta.'-furanyl, and hydroxy; R.sub.5 is H; A is CH.sub.2CH.sub.2;
Y is O or S; and Z is O or NH.
[0207] Another embodiment of the present invention is directed to a
compound of Formula (I) wherein R.sub.4 is preferably substituted
at the .alpha.'- or .beta.'-position of Formula (I).
[0208] Another embodiment of the present invention is directed to
compositions comprising a compound selected from the group
consisting of: [0209] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is 1H-imidazol-2-yl-methyl;
R.sup.4 is .alpha.'-hydroxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0210] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is furan-3-yl-methyl; R.sup.4 is
.alpha.'-hydroxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0211] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
.alpha.'-hydroxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0212] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
.alpha.'-methoxy; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0213] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is pyridin-2-yl-methyl; R.sup.4
is H; R.sup.5 is H; Y is O; A is --CH.sub.2CH.sub.2--; [0214] a
compound of Formula (I) wherein G is N,N-diethylaminocarbonyl;
R.sup.3 is furan-3-yl-methyl; R.sup.4 is H; R.sup.5 is H; Y is O;
and A is --CH.sub.2CH.sub.2--; [0215] a compound of Formula (I)
wherein G is N,N-diethylaminocarbonyl; R.sup.3 is
thien-2-yl-methyl; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0216] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is benzyl; R.sup.4 is H; R.sup.5
is H; Y is O; and A is --CH.sub.2CH.sub.2--; [0217] a compound of
Formula (I) wherein G is pyridin-3-yl; R.sup.3 is furan-3-yl
methyl; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0218] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is furan-2-yl methyl; R.sup.4 is
H; R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; [0219] a
compound of Formula (I) wherein G is N,N-diethylaminocarbonyl;
R.sup.3 is H; R.sup.4 is .alpha.'-methyl; R.sup.5 is H; Y is O; and
A is --CH.sub.2CH.sub.2--; [0220] a compound of Formula (I) wherein
G is N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
.alpha.'-phenyl; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0221] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is H; R.sup.5 is H;
Y is O; and A is --CH.sub.2CH.sub.2--; [0222] a compound of Formula
(I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is
H; R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; [0223] a
compound of Formula (I) wherein G is N,N-diethylaminocarbonyl;
R.sup.3 is H; R.sup.4 is .beta.''-bromo; R.sup.5 is H; Y is O; and
A is --CH.sub.2CH.sub.2--; [0224] a compound of Formula (I) wherein
G is N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is H; R.sup.5
is H; Y is O; and A is --CH.sub.2CH.sub.2--; [0225] a compound of
Formula (I) wherein G is N,N-diethylaminocarbonyl; R.sup.3 is H;
R.sup.4 is .alpha.'-chloro; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0226] a compound of Formula (I) wherein G is
N,N-diethylaminocarbonyl; R.sup.3 is H; R.sup.4 is R''-fluoro;
R.sup.5 is H; Y is O; and A is --CH.sub.2CH.sub.2--; [0227] a
compound of Formula (I) wherein G is 2-methylcarbonylamino-phenyl;
R.sup.3 is H; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--; [0228] a compound of Formula (I) wherein G is
pyrrolidin-1-yl; R.sup.3 is H; R.sup.4 is H; R.sup.5 is H; Y is O;
and A is --CH.sub.2CH.sub.2--; [0229] a compound of Formula (I)
wherein G is N,N-diethylaminocarbonyl; R.sup.3 is
furan-3-yl-methyl; R.sup.4 is H; R.sup.5 is H; Y is O; and A is
--CH.sub.2CH.sub.2--;
[0230] Another embodiment of the present invention is directed to
compounds and compositions comprising a compound selected from the
group consisting of: [0231]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0232]
(3-Hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazin-3-yl]-methanone; [0233]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl-phenethyl-amide; [0234]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne; [0235]
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(-
1H-tetrazol-5yl)-10H-phenoxazine; [0236]
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-1-
0H-phenoxazine; [0237]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile;
[0238]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-10H-phenoxazine-
-3-carboxamidine; [0239]
Endo-N,N-Diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazine-3-carboxamidine; [0240]
Endo-N,N-Diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxamidine; [0241]
Endo-3-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]-
oxadiazol-5-one; [0242]
endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid amide; [0243]
Endo-3-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenox-
azin-3-yl]-4H-[1,2,4]oxadiazol-5-one; [0244]
Endo-3-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl-
]-4H-[1,2,4]oxadiazol-5-one; [0245]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0246]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide; [0247]
6-Methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide; [0248]
6-Hydroxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide; [0249]
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid diethylamide; [0250]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-pheno-
xazine; [0251]
N,N-Diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3--
carboxamidine; [0252]
3-[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,-
2,4]oxadiazol-5-one; [0253]
10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-p-
henothiazine; [0254]
N-{2-[10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiaz-
in-3-yl]-phenyl}-acetamide; [0255]
10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-3-yl--
10H-phenothiazine; [0256]
3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine; [0257]
10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-4-yl--
10H-phenothiazine; [0258]
3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine; [0259]
3-Pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10-
H-phenothiazine; [0260]
N-{2-[10-(8-Allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-ph-
enyl}-acetamide; [0261]
N-{2-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl-
]-phenyl}-acetamide; [0262]
N-(2-{10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-ph-
enothiazin-3-yl}-phenyl)-acetamide; [0263]
N-{2-[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-p-
henyl}-acetamide; [0264]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenothiazine;
[0265]
N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-phe-
nyl}-acetamide; [0266]
10-(8-Allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenothiazin-
e; [0267] Endo-10-(8-Aza-bicyclo[3.2.1
]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine; [0268]
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phe-
noxazine; [0269]
Endo-3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazine; [0270]
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl--
10H-phenoxazine; [0271]
Endo-3-Pyridin-3-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine; [0272] Endo-10-(8-Aza-bicyclo[3.2.1
]oct-3-yl)-3-chloro-10H-phenoxazine; [0273]
Endo-10-(8-Aza-bicyclo[3.2.1
]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine; [0274]
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phe-
noxazine; [0275]
Endo-3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazine; [0276]
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl--
10H-phenoxazine; [0277]
Endo-3-Pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine; [0278]
Exo-3-(3-Pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester; [0279]
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phen-
oxazine; [0280]
Exo-3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazine; [0281]
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-1-
0H-phenoxazine; [0282]
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-10H-phenoxazine;
[0283]
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine;
[0284]
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-1-
0H-phenoxazine; [0285]
Exo-3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazine; [0286]
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-1-
0H-phenoxazine; [0287]
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazin-
e; [0288]
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonit-
rile; [0289]
Exo-3-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]o-
xadiazol-5-one; [0290]
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rbonitrile; [0291]
6-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rbonitrile; [0292] [10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenothiazin-3-yl]-pyrrolidin-1-yl-methanone; [0293]
[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-pyr-
rolidin-1-yl-methanone; [0294]
{10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenothiaz-
in-3-yl}-pyrrolidin-1-yl-methanone; [0295]
[10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3--
yl)-10H-hydroxy-pyrrolidin-1-yl)-methanone; [0296]
(3-Hydroxy-pyrrolidin-1-yl)-[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenothiazin-3-yl]-methanone; [0297]
{10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenothiaz-
in-3-yl}-(3-methyl-pyrrolidin-1-yl)-methanone; [0298]
[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-pyrrol-
idin-1-yl-methanone; [0299]
(3-Hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenothiazin-3-yl]-methanone; [0300]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide; [0301]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0302]
Endo-10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxaz-
ine-3-carboxylic acid diethylamide; [0303]
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide; [0304]
Endo-10-(8-Thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide; [0305]
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide; [0306]
Endo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide; [0307]
Endo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenox-
azine-3-carboxylic acid diethylamide; [0308]
Endo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phe-
noxazine-3-carboxylic acid diethylamide; [0309]
Endo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxy-
lic acid diethylamide; [0310]
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0311]
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbo-
xylic acid diethylamide; [0312]
Exo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide; [0313]
Exo-10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide; [0314]
Exo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenoxa-
zine-3-carboxylic acid diethylamide; [0315]
Exo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide; [0316]
Exo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxyl-
ic acid diethylamide; [0317]
Exo-10-(8-Thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide; [0318]
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine--
3-carboxylic acid diethylamide; [0319]
Exo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phen-
oxazine-3-carboxylic acid diethylamide; [0320]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenoxazin-4-ol-
; [0321]
Endo-7-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]-
oct-3-yl)-10H-phenoxazin-4-ol; [0322]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-6-methoxy-10H-phenoxazine-
; [0323]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-1-
0H-phenoxazine; [0324]
Endo-6-Methoxy-3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine; [0325]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazin-4-ol-
; [0326]
Endo-7-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]-
oct-3-yl)-10H-phenoxazin-4-ol; [0327]
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phe-
noxazin-4-ol; [0328]
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-4-yl-10H-pheno-
xazine; [0329]
Endo-6-Methoxy-3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine; [0330] Endo-6-M
ethoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-p-
henoxazine; [0331]
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide; [0332]
Endo-N-{2-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-
-yl]-phenyl}-acetamide; [0333]
Endo-N-{2-[10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enoxazin-3-yl]-phenyl}-acetamide; [0334]
Endo-N-{2-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phe-
noxazin-3-yl]-phenyl}-acetamide; [0335]
Exo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}--
acetamide; [0336]
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenoxazin-3-y-
l]-phenyl}-acetamide; [0337]
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazin-3-y-
l]-phenyl}-acetamide; [0338]
10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-ph-
enothiazine; [0339]
10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-y-
l)-10H-phenothiazine; [0340]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine;
[0341]
N,N-Diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phen-
othiazine-3-carboxamidine; [0342]
N,N-Diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enothiazine-3-carboxamidine; [0343]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-pheno-
thiazine; [0344]
N,N-Diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine--
3-carboxamidine; [0345]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-10H-phenothiaz-
ine; [0346]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenothiazin-4-ol;
[0347]
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothia-
zine-3-carboxylic acid diethylamide; [0348]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenothiazine-3-carboxyli-
c acid diethylamide; [0349]
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenothiazine-3-carboxyli-
c acid diethylamide; and [0350] enantiomers, diastereomers,
tautomers, solvates, or pharmaceutically acceptable salts
thereof.
[0351] Another embodiment of the present invention is a composition
comprising the dextrorotatory enantiomer of a compound of formula
(I), wherein said composition is substantially free from the
levorotatory isomer of said compound. In the present context,
substantially free means less than 25%, preferably less than 10%,
more preferably less than 5%, even more preferably less than 2% and
even more preferably less than 1% of the levorotatory isomer
calculated as.
% levorotatory = ( mass levorotatory ) ( mass dextrorotatory ) + (
mass levorotatory ) .times. 100 ##EQU00001##
[0352] Another embodiment of the present invention is a composition
comprising the levorotatory enantiomer of a compound of formula (I)
wherein said composition is substantially free from the
dextrorotatory isomer of said compound. In the present context,
substantially free from means less than 25%, preferably less than
10%, more preferably less than 5%, even more preferably less than
2% and even more preferably less than 1% of the dextrorotatory
isomer calculated as
% dextrorotatory = ( mass dextrorotatory ) ( mass dextrorotatory )
+ ( mass levorotatory ) .times. 100 ##EQU00002##
[0353] In certain embodiments, the present invention provides the
endo isomer of a compound of formula (I) wherein said compound is
substantially free from the exo isomer of said compound. In certain
embodiments, the present invention provides compositions comprising
the endo isomer of a compound of formula (I) wherein said
composition is substantially free from the exo isomer of said
compound. In the present context, substantially free means less
than 25%, preferably less than 10%, more preferably less than 5%,
even more preferably less than 2% and even more preferably less
than 1% of the exo isomer.
[0354] In certain embodiments, the present invention provides the
exo isomer of a compound of formula (I) wherein said compound is
substantially free from the endo isomer of said compound. In
certain embodiments, the present invention provides compositions
comprising the exo isomer of a compound of formula (I) wherein said
composition is substantially free from the endo isomer of said
compound. In the present context, substantially free means less
than 25%, preferably less than 10%, more preferably less than 5%,
even more preferably less than 2% and even more preferably less
than 1% of the endo isomer.
[0355] In other embodiments, compositions of the present invention
comprise a mixture of the exo and endo isomers of a compound of
formula (I).
[0356] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts" (Ref. International
J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (January), 66,
1, 1). Other salts well known to those in the art may, however, be
useful in the preparation of compounds according to this invention
or of their pharmaceutically acceptable salts. Representative
organic or inorganic acids include, but are not limited to,
hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric,
phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,
fumaric, malic, tartaric, citric, benzoic, mandelic,
methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic,
pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,
cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic
acid. Representative organic or inorganic bases include, but are
not limited to, basic or cationic salts such as benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc.
[0357] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0358] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0359] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0360] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0361] Even though the compounds of the present invention
(including their pharmaceutically, acceptable salts and
pharmaceutically acceptable solvates) can be administered alone,
they will generally be administered in admixture with a
pharmaceutical carrier, excipient or diluent selected with regard
to the intended route of administration and standard pharmaceutical
or veterinary practice. Thus, the present invention is directed to
pharmaceutical and veterinary compositions comprising compounds of
Formula (I) and one or more pharmaceutically acceptable carriers,
excipients or diluents.
[0362] By way of example, in the pharmaceutical and veterinary
compositions of the present invention, the compounds of the present
invention may be admixed with any suitable binder(s), lubricant(s),
suspending agent(s), coating agent(s), and/or solubilising
agent(s).
[0363] Tablets or capsules of the compounds may be administered
singly or two or more at a time, as appropriate. It is also
possible to administer the compounds in sustained release
formulations.
[0364] Alternatively, the compounds of the general Formula (I) can
be administered by inhalation or in the form of a suppository or
pessary, or they may be applied topically in the form of a lotion,
solution, cream, ointment or dusting powder. An alternative means
of transdermal administration is by use of a skin patch. For
example, they can be incorporated into a cream consisting of an
aqueous emulsion of polyethylene glycols or liquid paraffin. They
can also be incorporated, at a concentration of between 1 and 10%
by weight, into an ointment consisting of a white wax or white soft
paraffin base together with such stabilizers and preservatives as
may be required.
[0365] For some applications, preferably the compositions are
administered orally in the form of tablets containing excipients
such as starch or lactose, or in capsules or ovules either alone or
in admixture with excipients, or in the form of elixirs, solutions
or suspensions containing flavoring or coloring agents.
[0366] The compositions (as well as the compounds alone) can also
be injected parenterally, for example intracavernosally,
intravenously, intramuscularly or subcutaneously. In this case, the
compositions will comprise a suitable carrier or diluent.
[0367] For parenteral administration, the compositions are best
used in the form of a sterile aqueous solution which may contain
other substances, for example enough salts or monosaccharides to
make the solution isotonic with blood.
[0368] For buccal or sublingual administration the compositions may
be administered in the form of tablets or lozenges which can be
formulated in a conventional manner.
[0369] By way of further example, pharmaceutical and veterinary
compositions containing one or more of the compounds of the
invention described herein as the active ingredient can be prepared
by intimately mixing the compound or compounds with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending upon the desired route of administration (e.g.,
oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
the major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0370] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those skilled in that art. To be administered in the form of a
transdermal delivery system, the dosage administration will, of
course, be continuous rather than intermittent throughout the
dosage regimen.
[0371] It is also apparent to one skilled in the art that the
therapeutically effective dose for active compounds of the
invention or a pharmaceutical composition thereof will vary
according to the desired effect. Therefore, optimal dosages to be
administered may be readily determined and will vary with the
particular compound used, the mode of administration, the strength
of the preparation, and the advancement of the disease condition.
In addition, factors associated with the particular subject being
treated, including subject age, weight, diet and time of
administration, will result in the need to adjust the dose to an
appropriate therapeutic level. The above dosages are thus exemplary
of the average case. There can, of course, be individual instances
where higher or lower dosage ranges are merited, and such are
within the scope of this invention.
[0372] Compounds of this invention may be administered in any of
the foregoing compositions and dosage regimens or by means of those
compositions and dosage regimens established in the art whenever
use of the compounds of the invention as analgesics is required for
a subject in need thereof.
[0373] The invention also provides a pharmaceutical or veterinary
pack or kit comprising one or more containers filled with one or
more of the ingredients of the pharmaceutical and veterinary
compositions of the invention. Optionally associated with such
container(s) can be a notice in the form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals or biological products, which notice reflects
approval by the agency of manufacture, use or sale for human
administration.
[0374] The compounds of the present invention may be used to treat
mild to severe pain in warm-blooded animals such as humans by
administration of an analgesically effective dose. The dosage range
would be from about 0.1 mg to about 15,000 mg, in particular from
about 50 mg to about 3500 mg or, more particularly from about 100
mg to about 1000 mg of active ingredient in a regimen of about 1 to
4 times per day for an average (70 kg) human; although, it is
apparent to one skilled in the art that the therapeutically
effective amount for active compounds of the invention will vary as
will the types of pain being treated.
[0375] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing 0.01, 10.0,
50.0, 100, 150, 200, 250, and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
subject to be treated.
[0376] Examples of pain intended to be within the scope of the
present invention include, but are not limited to, inflammatory
pain, centrally mediated pain, peripherally mediated pain, visceral
pain, structural or soft tissue injury related pain, progressive
disease related pain, neuropathic pain and acute pain such as
caused by acute injury, trauma or surgery and chronic pain such as
headache and that caused by neuropathic conditions, post-stroke
conditions, cancer, and migraine.
[0377] Compounds of the present invention are also useful as
immunosuppressants, antiinflammatory agents, agents for the
treatment and prevention of neurological and psychiatric
conditions, for instance, depression and Parkinson's disease,
agents for the treatment of urological and reproductive conditions,
for instance, urinary incontinence and premature ejaculation,
medicaments for drug and alcohol abuse, agents for treating
gastritis and diarrhea, cardiovascular agents and cardioprotective
agents and agents for the treatment of respiratory diseases.
[0378] The compounds of the present invention are also useful in
treating pain caused by osteoarthritis, rheumatoid arthritis,
fibromyalgia, migraine, headache, toothache, burn, sunburn, snake
bite (in particular, venomous snake bite), spider bite, insect
sting, neurogenic bladder, benign prostatic hypertrophy,
interstitial cystitis, rhinitis, contact
dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,
enteritis, cellulites, causalgia, sciatic neuritis, mandibular
joint neuralgia, peripheral neuritis, polyneuritis, stump pain,
phantom limb pain, post-operative ileus, cholecystitis,
postmastectomy pain syndrome, oral neuropathic pain, Charcot's
pain, reflex sympathetic dystrophy, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, post-herpetic
neuralgia, trigeminal neuralgia, cluster headache, migraine
headache, peripheral neuropathy, bilateral peripheral neuropathy,
diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia,
optic neuritis, postfebrile neuritis, migrating neuritis, segmental
neuritis, Gombault's neuritis, neuronitis, cervicobrachial
neuralgia, cranial neuralgia, geniculate neuralgia,
glossopharyngial neuralgia, migrainous neuralgia, idiopathic
neuralgia, intercostals neuralgia, mammary neuralgia, Morton's
neuralgia, nasociliary neuralgia, occipital neuralgia, red
neuralgia, Sluder's neuralgia, splenopalatine neuralgia,
supraorbital neuralgia, vidian neuralgia, inflammatory bowel
disease, irritable bowel syndrome, sinus headache, tension
headache, labor, childbirth, menstrual cramps, and cancer.
[0379] In regard to the use of the present compounds in treatment
of the diseases or conditions such as those listed above, a
therapeutically effective dose can be determined by persons skilled
in the art by the use of established animal models. Such a dose
would likely fall in the range of from about 0.01 mg to about
15,000 mg of active ingredient administered 1 to 4 times per day
for an average (70 kg) human.
General Synthetic Methods
[0380] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated in the schemes that follow.
Since the schemes are an illustration, the invention should not be
construed as being limited by the chemical reactions and conditions
expressed. The preparation of the various starting materials used
in the schemes is well within the skill of persons versed in the
art.
##STR00006## ##STR00007##
[0381] The preparation of compounds of this invention is
illustrated in Schemes 1 through 11. The overall strategy in Scheme
1 is based on the synthesis of appropriately substituted compounds
of formula 1.4 (Y.dbd.O, S) that are condensed with an
appropriately substituted compound of formula 1.5. In compounds of
formula 1.5, X.sub.2 and X.sub.3 can each be a halogen atom,
trifluoromethanesulfonyloxy or a nitro group. In stage 1.1, a
bridged N1-protected 4-aminopiperidine 1.1 is condensed with a
properly substituted O-protected phenol (Y.dbd.O) or thiophenol
(Y.dbd.S) 1.2. The protective group on the N1 nitrogen of 1.1
(represented as P) may include an alkanyl, alkenyl or aralkanyl
group in which case they are the therapeutically useful products of
this invention. The group P may also be trifluoromethylcarbonyl,
alkoxycarbonyl or aralkoxycarbonyl. Bridge A may include
(CH.sub.2).sub.2 and (CH.sub.2).sub.3. Useful phenol or thiophenol
protective groups (R) include lower alkyl groups, benzyl,
trialkylsilyl and the like. Appropriate substituents on the
protected phenol or thiophenol in the 2-position (X.sub.1) may
include halogens and trifluoromethanesulfonyloxy. The Q group in
the 5-position may be a substituent such as fluoro, chloro, bromo,
cyano, iodo, carboxy, dialkylaminosulfonyl or
trifluoromethanesulfonyloxy. Stage 1.2 includes deprotection of the
phenol or thiophenol protective group. Such transformations may
include the dealkylation of lower alkyl ethers to give their
corresponding alcohols using reagents such as boron trihalides, or
dealkylation of lower alkyl thioethers using reagents such as
Na/NH.sub.3. A benzyl protective group may be removed under
conditions of hydrogenation in the presence of a transition metal
such as palladium. Trialkylsilyl protective groups may be removed
by treatment with a source of fluoride anion such as tetrabutyl
ammonium fluoride, or by exposure to an inorganic acid such as
aqueous hydrogen chloride and the like.
[0382] In stage 1.3, hydroxyaniline (Y.dbd.O) or thioaniline
(Y.dbd.S) 1.4 may be condensed with an appropriately substituted
benzene moiety 1.5. Substituents X.sub.2 and X.sub.3 may include
halogens, trifluoromethanesulfonyloxy, or a nitro group. Useful
coupling conditions of the anilino nitrogen with a compound of
formula 1.5 include palladium catalyzed condensations in the
presence of a phosphine ligand such as Pd.sub.2(dba).sub.3 and a
base such as cesium carbonate. Coupling of the hydroxy or thio
moiety with the remaining substituted phenyl group may proceed
using Ullmann type coupling conditions. In addition, the two steps
described in stage 1.3 may be reversed with biaryl ether or biaryl
thioether formation preceding the formation of the biaryl amine.
Alternatively, the condensation between compounds of formula 1.4
and compounds of formula 1.5 to yield compounds of formula 1.6 in
one step may be affected by treatment with an inorganic base such
as potassium carbonate in a suitable solvent such as dimethyl
formamide.
[0383] The regiochemical outcome of the condensation between
compounds of formula 1.4 and compounds of formula 1.5 depends on
the position of the R4 substituent in compounds of formula 1.5 and
on the reaction conditions used for the condensation. An extensive
review on this topic is available in the literature (see, for
example: The Smiles and Related Rearrangements of aromatic Systems'
by W. E. Truce, E. M. Kreider, and W. W. Brand in Organic
Reactions, 1970, Vol. 18, pp. 99-215).
[0384] The protective group P can be removed to obtain secondary
amines 1 as illustrated for Stage 1.4. These transformations may be
carried out using certain acidic reagents such as hydrogen bromide
or trimethylsilyl iodide. Phenoxazines (Y.dbd.O) or phenothiazines
(Y.dbd.S) of type 1.6 bearing readily cleavable groups such as
methyl, allyl or benzyl may be transformed into the aforementioned
alkoxycarbonyl derivatives by treatment with alkanylchloroformates
such as ethyl chloroformate or 1-chloroethyl chloroformate and thus
serve as sources of phenoxazines and phenothiazines 1. Phenoxazines
or phenothiazines of type 1.6 bearing a trifluormethylcarbonyl
group may be treated with potassium carbonate in an alcoholic
solvent such as methanol to yield phenoxazines and phenothiazines
1.
[0385] Finally the secondary amines 1 may be converted to a
compound of formula 2 as shown in Stage 1.5. These transformations
may be carried out by reductive alkylation using a carbonyl
compound and a reducing agent such as sodium borohydride, sodium
cyanoborohydride, sodium triacetoxyborohydride, or
tetramethylammonium triacetoxyborohydride. They may also be carried
out by alkylation using an alkanyl, alkenyl or aralkyl halide and
an organic or inorganic base.
[0386] The Q function in compounds 1 or 2 may be converted into
group G, which may be --C(Z)NR.sub.1 R.sub.2, an aryl substituent,
or an appropriate heterocycle as defined herein, to give compounds
of formula I. When the Q function is a halogen or
trifluoromethanesulfonyloxy, it may be converted to an ester via
alkoxycarbonylation using carbon monoxide, an aliphatic alcohol, a
trialkanyl amine, and a palladium catalyst such as
bis(triphenylphosphine) palladium(II)dichloride. Subsequently, when
Q is an ester, the ester may be hydrolyzed to a carboxylic acid.
The carboxylic acid may then be coupled with ammonia, a primary
amine, or a secondary amine to form a primary, secondary or
tertiary amide, respectively. Alternatively, the conversion of a
carboxylic acid to an amide may be carried out via an acid chloride
using thionyl chloride, oxalyl chloride, or the like, followed by a
Schotten-Baumann reaction using ammonia or an amine in the presence
of an alkali metal hydroxide. Alternatively, the conversion of a
carboxylic acid to an amide may be carried out via the use of
peptide coupling agents such as 1,3-dicyclohexylcarbondiimide
(DCC), O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium
hexafluorophosphate (HATU),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), or the like. Alternatively, the ester
may be converted directly to the amide by the action of a
dimethylaluminum amide.
[0387] Alternatively, when the Q function is a halogen or
trifluoromethanesulfonyloxy, it may be converted directly to an
amide via aminocarbonylation using a carbon monoxide source such as
molybdenum hexacarbonyl, an appropriate amine, and a palladium
catalyst such as Hermann's catalyst.
[0388] Alternatively, one may effect the transformation of the
group Q to a substituent G (wherein G is an amidino or heterocycle)
by way of a nitrile. Synthesis of the nitrile may be accomplished
by treatment of the compounds 1 or 2 (when Q is bromo or
trifluoromethanesulfonyloxy) with Zn(CN).sub.2 and a palladium
catalyst such as (Ph.sub.3P).sub.4Pd or by treatment of the
compounds 1 or 2 with CuCN at elevated temperatures. For the
synthesis of amidino functional groups, the nitrile is treated with
hydroxylamine under basic conditions to afford an oxime. Treatment
of the oxime with a primary or secondary amine, CuCl, and an alkali
metal carbonate under microwave irradiation in an alcoholic solvent
provides the amidino compounds of the present invention. Microwave
accelerated reactions may be performed using either a CEM Discover
or a Personal Chemistry Smith Synthesizer microwave instrument. The
oxime described above is instrumental in the preparation of
compounds wherein G is a heterocycle. The oxime may be cyclized
with a variety of electrophiles known to one versed in the art to
give the heterocycles of the present invention. For instance,
reaction of an oxime with CDI provides oxadiazolones, and treatment
of the oxime with TCDI provides the corresponding
oxadiazolethiones. Similarly, the treatment of the oxime with
thionyl chloride in the presence of a tertiary amine gives
oxathiadiazoles of the present invention.
[0389] Alternatively, compounds where Q is a halogen atom or a
trifluoromethanesulfonyloxy group may participate in transition
metal-mediated coupling reactions such as Suzuki, Stille or Negishi
chemistry. Desired end products of the present invention may
include chemical modifications at R.sub.4. Such transformations may
include the dealkylation of lower alkyl ethers to give the
corresponding alcohols using reagents such as boron trihalides.
Compounds where R.sub.4 is a halogen atom may participate in
transition metal-mediated coupling reactions such as Suzuki, Stille
or Negishi chemistry.
##STR00008##
[0390] Scheme 2 outlines an alternative approach to the synthesis
of phenoxazines (Y.dbd.O) or phenothiazines (Y.dbd.S) 1.6. In this
scheme, an appropriately substituted phenol (Y.dbd.O) or thiophenol
(Y.dbd.S) of type 2.2 is reacted with an appropriately substituted
benzene moiety 2.1 in the presence of a base, such as potassium
carbonate or sodium hydroxide in an organic solvent, such as
dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or the
like as shown in stage 2.1. Appropriate substituents X.sub.1 and
X.sub.2 in this scheme may include halogens and
trifluoromethanesulfonyloxy. In stage 2.2, the nitro functionality
is reduced to the corresponding amine. This reduction can be
accomplished via treatment with tin(II) chloride in an alcoholic
solvent such as ethanol. Stage 2.3 depicts the conversion of
primary aniline 2.4 to secondary aniline 2.6, which can be
accomplished via reductive alkylation using a carbonyl compound 2.5
and a reducing agent such as sodium borohydride, sodium
cyanoborohydride, sodium triacetoxyborohydride, or
tetramethylammonium triacetoxyborohydride. Stage 2.4 depicts
formation of compounds of formula 1.6, which can be accomplished by
treatment of secondary aniline 2.6 with an appropriate base such as
potassium carbonate.
##STR00009##
[0391] Scheme 3 illustrates an alternative synthesis of compound
2.3. In this approach, an appropriately substituted 2-nitrophenol
(Y.dbd.O) or 2-nitrothiophenol (Y.dbd.S) may be condensed with an
appropriately substituted benzene moiety of type 3.2 under Ullmann
type coupling conditions. Appropriate substituents X.sub.1 and
X.sub.2 include halogens and trifluoromethanesulfonyloxy.
##STR00010##
[0392] Scheme 4 illustrates an alternative approach to the
synthesis of phenoxazines (Y.dbd.O) or phenothiazines (Y.dbd.S)
1.6. Condensation of appropriately substituted phenols (Y.dbd.O) or
thiophenols (Y.dbd.S) 2.2 with substituted benzene moiety 1.5 under
Ullmann type coupling conditions as shown in stage 4.1 may result
in the formation of biaryl ethers (Y.dbd.O) or biaryl thioethers
(Y.dbd.S) 4.1. Appropriate X.sub.1, X.sub.2 and X.sub.3
substituents may include halogens and trifluoromethanesulfonyloxy.
Palladium catalyzed condensation of biaryl ethers or biaryl
thioethers 4.1 with bridged N1-protected 4-aminopiperidines 1.1 in
the presence of a phosphine ligand such as Pd.sub.2(dba).sub.3 and
a base such as cesium carbonate is shown in stage 4.2 may result in
the formation of phenoxazines or phenothiazines 1.6.
##STR00011##
[0393] An alternative approach to the synthesis of intermediate 4.1
is depicted in Scheme 5 and is based on the reaction of
appropriately substituted phenols (Y.dbd.O) or thiophenols
(Y.dbd.S) 5.1 with an appropriately substituted benzene moiety 3.2
under Ullmann type coupling conditions (stage 5.1). Substituents
X.sub.1, X.sub.2, and X.sub.3 may include halogens or
trifluoromethanesulfonyloxy.
##STR00012##
[0394] Scheme 6 illustrates an alternative approach to the
synthesis of intermediates 2.6. An appropriately substituted
compound of formula 1.5 may be reacted with bridged N1-protected
4-aminopiperidines 1.1 in the presence of a palladium catalyst such
as Pd.sub.2(dba).sub.3, a phosphine ligand and a base such as
cesium carbonate as shown in stage 6.1. Appropriate X.sub.1 and
X.sub.2 substituents may include halogens and
trifluoromethanesulfonyloxy. Compounds of formula 6.1 may then be
reacted with appropriately substituted phenols (Y.dbd.O) or
thiophenols (Y.dbd.S) 2.2 under Ullmann type coupling conditions to
yield anilines 2.6 as shown in stage 6.2.
##STR00013##
[0395] Scheme 7 illustrates an alternative approach to the
synthesis of phenoxazines (Y.dbd.O) or phenothiazines (Y.dbd.S)
1.6. Condensation of appropriately substituted compounds of formula
3.2 with bridged N1-protected 4-aminopiperidines 1.1 may result in
formation of intermediate 7.1 as shown in stage 7.1. Appropriate
X.sub.1, X.sub.2, and X.sub.3 substituents may include halogens and
trifluoromethanesulfonyloxy. Reaction of compounds 7.1 with
appropriately substituted phenol (Y.dbd.O) or thiophenols (Y.dbd.S)
7.2 under Ullmann like coupling conditions may result in formation
of compounds 7.3 as shown in stage 7.2. Finally, ring closure of
compounds 7.4 may be accomplished in the presence of a palladium
catalyst such as Pd.sub.2(dba).sub.3, a phosphine ligand such as
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xant phos) and a
base such as potassium tert-butoxide or cesium carbonate as shown
in stage 7.3.
##STR00014##
[0396] Scheme 8 illustrates an alternative synthesis of
phenoxazines (Y.dbd.O) or phenothiazines (Y.dbd.S) 1.6 and is based
on an Ullmann-like coupling of bridged N1-protected
4-aminopiperidines 1.1 with appropriately substituted and protected
phenols (Y.dbd.O) or thiophenols (Y.dbd.S) 8.1 as shown in stage
8.1. Useful phenol or thiophenol protective groups for compounds
8.1 include lower alkyl groups, benzyl, trialkylsilyl and the like.
Appropriate X.sub.1, X.sub.2, and X.sub.3 substituents may include
halogens and trifluoromethanesulfonyloxy. The resulting compounds
8.2 may be condensed with appropriately functionalized benzene
compounds 3.2 to yield diarylanilines 8.3. Stage 8.3 includes
deprotection of the phenol or thiophenol protective group. Such
transformations may include the dealkylation of lower alkyl ethers
to give their corresponding alcohols using reagents such as boron
trihalides or the dealkylation of the alkyl thioethers using
Na/NH.sub.3. A benzyl protective group may be removed under
conditions of hydrogenation in the presence of a transition metal
such as palladium. Trialkylsilyl protective groups may be removed
by treatment with a source of fluoride anion such as tetrabutyl
ammonium fluoride, or by exposure to an inorganic acid such as
aqueous hydrogen chloride and the like. Finally, ring closure of
compounds 8.3 to phenoxazines or phenothiazines 1.6 may be
accomplished via an Ullmann type transformation as shown in stage
8.4.
##STR00015##
[0397] Scheme 9 illustrates another synthetic approach to compounds
7.4. Displacement of X.sub.1 in appropriately substituted compounds
of formula 9.2 with appropriately substituted compounds of formula
9.1 as shown in stage 9.1 may lead to biaryl ethers (Y.dbd.O) and
biarylthioethers (Y.dbd.S) 9.3. Appropriate X.sub.1 and X.sub.2
substituents may include halogens and trifluoromethanesulfonyloxy.
Reduction of compounds 9.3 to amines 9.4 as shown in stage 9.2 may
be accomplished using tin(II) chloride in an alcoholic solvent such
as ethanol. Stage 9.3 depicts the conversion of primary anilines
9.4 to secondary anilines 7.4 and can be accomplished via reductive
alkylation using a carbonyl compounds 2.5 and a reducing agent such
as sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, or tetramethylammonium
triacetoxyborohydride.
##STR00016##
[0398] Scheme 10 illustrates another synthetic approach to
compounds 9.3. For construction of diaryl ethers (Y.dbd.O) and
diaryl thioethers (Y.dbd.S) 9.3, appropriately substituted
2-hydroxynitrobenzenes or 2-thionitrobenzenes 10.1 may be caused to
react with appropriately substituted compounds of formula 1.5 under
Ullmann type conditions as shown in stage 10.1. Appropriate X.sub.2
and X.sub.3 substituents may include halogens and
trifluoromethanesulfonyloxy.
##STR00017##
[0399] Scheme 11 illustrates another synthetic approach to
compounds 1.6. Stage 11.1 depicts the conversion of appropriately
substituted 2-hydroxyanilines (Y.dbd.O) 11.1 to compounds 11.2
(Y.dbd.O), which can be accomplished via reductive alkylation using
a carbonyl compound 2.5 and a reducing agent such as sodium
borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,
or tetramethylammonium triacetoxyborohydride. Appropriately
substituted 2-hydroxyanilines 11.2 may be caused to react with an
appropriately substituted benzene 3.2 under Ullmann type conditions
or under basic conditions such as potassium carbonate in DMF (when
X.sub.1.dbd.NO.sub.2) as shown in stage 11.3 to yield compounds of
formula 1.6. Appropriate X.sub.1 and X.sub.2 substituents may
include halogens, trifluoromethanesulfonyloxy, and a nitro
group.
[0400] The regiochemical outcome of the condensation of compounds
of formula 11.2 with compounds of formula 3.2 depends on the
position of the Q substituent in compounds of formula 3.2 and on
the reaction conditions used for the condensation. An extensive
review on this topic is available in the literature (see, for
example: The Smiles and Related Rearrangements of aromatic Systems'
by W. E. Truce, E. M. Kreider, and W. W. Brand in Organic
Reactions, 1970, Vol. 18, pp. 99-215).
[0401] In compounds of formula 11.1 where Y is sulfur, an
intermediate spiro compound of formula 11.3 may be formed.
Compounds of formula 11.3 may be converted to compounds of formula
11.2 (Y.dbd.S) by treatment with a hydride reagent such as lithium
aluminum hydride or sodium borohydride.
[0402] In the above Schemes 1 through 11, the Q function of
compounds 2 may be converted into group G, which may be
--C(Z)NR.sub.1 R.sub.2, an aryl substituent, or an appropriate
heterocycle as defined herein, to give compounds of formula 3. When
the Q function of compounds 2 is a halogen or
trifluoromethanesulfonyloxy, it may be converted to an ester via
alkoxycarbonylation using carbon monoxide, an aliphatic alcohol, a
trialkanyl amine, and a palladium catalyst such as
bis(triphenylphosphine) palladium(I1)dichloride. Subsequently, when
Q is an ester, the ester may be hydrolyzed to a carboxylic acid.
The carboxylic acid may then be coupled with ammonia, a primary
amine, or a secondary amine to form a primary, secondary or
tertiary amide, respectively. Alternatively, the conversion of a
carboxylic acid to an amide may be carried out via an acid chloride
using thionyl chloride, oxalyl chloride, or the like, followed by a
Schotten-Baumann reaction using ammonia or an amine in the presence
of an alkali metal hydroxide. Alternatively, the conversion of a
carboxylic acid to an amide may be carried out via the use of
peptide coupling agents such as 1,3-dicyclohexylcarbondiimide
(DCC), O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium
hexafluorophosphate (HATU),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), or the like. Alternatively, the ester
may be converted directly to the amide by the action of a
dimethylaluminum amide.
[0403] Instead of proceeding to compounds 3 via an ester, one may
effect the transformation of the group Q to a substituent G
(wherein G is an amidino or heterocycle) by way of a nitrile.
Synthesis of the nitrile may be accomplished by treatment of the
compounds 2 (when Q is bromo or trifluoromethanesulfonyloxy) with
Zn(CN).sub.2 and a palladium catalyst such as (Ph.sub.3P).sub.4Pd
or by treatment of the compounds 2 with CuCN at elevated
temperatures. For the synthesis of amidino functional groups, the
nitrile is treated with hydroxylamine under basic conditions to
afford an oxime. Treatment of the oxime with a primary or secondary
amine, CuCl, and an alkali metal carbonate under microwave
irradiation in an alcoholic solvent provides the amidino compounds
of the present invention. Microwave accelerated reactions may be
performed using either a CEM Discover or a Personal Chemistry Smith
Synthesizer microwave instrument. The oxime described above is
instrumental in the preparation of compounds wherein G is a
heterocycle. The oxime may be cyclized with a variety of
electrophiles known to one versed in the art to give the
heterocycles of the present invention. For instance, reaction of an
oxime with CDI provides oxadiazolones, and treatment of the oxime
with TCDI provides the corresponding oxadiazolethiones. Similarly,
the treatment of the oxime with thionyl chloride in the presence of
a tertiary amine gives oxathiadiazoles of the present
invention.
[0404] An aryl substituent may be installed in place of the
functional group Q by coupling compounds 2 (when Q is bromo or
trifluoromethanesulfonyloxy) with a suitably substituted
arylboronic acid in the presence of a palladium catalyst and an
alkali metal carbonate.
[0405] Desired end products of the present invention may include
chemical modifications at R.sub.4. Such transformations may include
the dealkylation of lower alkyl ethers to give their corresponding
alcohols, using reagents such as boron trihalides. Compounds where
R.sub.4 is a halogen atom may participate in transition
metal-mediated coupling reactions such as Suzuki, Stille or Negishi
chemistry.
[0406] It is generally preferred that the respective product of
each process step be separated from other components of the
reaction mixture and subjected to purification before its use as a
starting material in a subsequent step. Separation techniques
typically include evaporation, extraction, precipitation and
filtration. Purification techniques typically include column
chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43,
2921), thin-layer chromatography, crystallization and distillation.
The structures of the final products, intermediates and starting
materials are confirmed by spectroscopic, spectrometric and
analytical methods including nuclear magnetic resonance (NMR), mass
spectrometry (MS) and liquid chromatography (HPLC). In the
descriptions for the preparation of compounds of this invention,
ethyl ether, tetrahydrofuran and dioxane are common examples of an
ethereal solvent; benzene, toluene, hexanes and heptanes are
typical hydrocarbon solvents and dichloromethane and dichloroethane
are representative halogenated hydrocarbon solvents. In those cases
where the product is isolated as the acid addition salt the free
base may be obtained by techniques known to those skilled in the
art. In those cases in which the product is isolated as an acid
addition salt, the salt may contain one or more equivalents of the
acid. Enantiomers of the compounds of the present invention may be
separated using chiral HPLC.
[0407] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described above and are illustrated more particularly in the
schemes that follow. Since the schemes are illustrations, the
invention should not be construed as being limited by the chemical
reactions and conditions expressed. The preparation of the various
starting materials used in the schemes is well within the skill of
persons versed in the art.
ABBREVIATIONS
[0408] AcOH=acetic acid [0409] Boc=tert-butoxycarbonyl [0410]
DIEA=N,N-diisopropyl-N-ethylamine [0411] DMF=N,N-dimethylformamide
[0412] DMSO=dimethyl sulfoxide [0413] Et=ethyl [0414] h=hour(s)
[0415] HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0416] K.sub.2CO.sub.3=potassium carbonate
[0417] Me=methyl [0418] min=minute(s) [0419] rt=room temperature
[0420] xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
[0421] Although the foregoing invention has been described in
detail by way of example for purposes of clarity of understanding,
it will be apparent to the artisan that certain changes and
modifications are comprehended by the disclosure and can be
practiced without undue experimentation within the scope of the
appended claims, which are presented by way of illustration not
limitation.
[0422] All publications and patent documents cited above are hereby
incorporated by reference in their entirety for all purposes to the
same extent as if each were so individually denoted.
Examples
Example A
##STR00018##
[0423] Procedure 1
3-Hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a
[0424] To a solution of 4-amino-3-hydroxybenzoic acid methyl ester
(2.0 g; 12 mmol) and 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (1.1
g; 10.8 mmol) in dichloroethane (30 mL) was added sodium
triacetoxyborohydride (3.2 g; 15.1 mmol) and acetic acid (0.65 mL;
11.4 mmol). The mixture was stirred at rt for 16 h. The mixture was
diluted with 1N NaHCO.sub.3 solution and chloroform was added. The
organic layer separated, and the aqueous phase was lyophilized. The
lyophilized residue was purified via reverse phase HPLC (eluent
gradient: 10 to 50% acetonitrile in water containing 0.1% TFA) to
yield 1.61 g (36.9%) of a mixture of endo and exo isomers of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a as a TFA salt. MS m/z (MH.sup.+) 291.
Procedure 2
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl ester, 2a
[0425] A mixture of the TFA salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a (0.424 g, 0.734 mmol), 2-fluoronitrobenzene
(95 .mu.L, 0.9 mmol) and potassium carbonate (564 mg, 4 mmol) in
DMF was heated to reflux for 70 min. The mixture was allowed to
cool to rt, filtered, and purified via reverse phase HPLC to yield
440 mg (88%) of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl ester, 2a, as TFA salt. MS m/z (MH.sup.+) 365.1.
Procedure 3
10-(8-Methyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid, 3a
[0426] To a solution of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl ester, 2a (440 mg, 0.646 mmol) in THF (5 mL) was added
1N NaOH (5 mL), and the mixture was stirred for 3 hr at rt. The
solvent was removed, the residue was dissolved in DMF and acidified
with a 2N TFA solution, and purified via reverse phase HPLC to
yield 295 mg (63%) of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid, 3a, as a TFA salt. MS m/z (MH.sup.+) 351.1.
Procedure 4
10-(8-Methyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4a
[0427] To a solution of the TFA salt of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid 3a (65 mg, 0.14 mmol) and HBTU (64 mg; 0.17 mmol) in DMF (2
mL) was added triethylamine (69 .mu.L, 0.43 mmol). The mixture was
stirred for 1 hr at rt, and purified without prior quenching via
reverse phase HPLC (eluent gradient: acetonitrile in water
containing 0.1% TFA) to yield 44.4 mg (61%) of title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 4a as a TFA salt. MS m/z (MH.sup.+) 406.2.
##STR00019##
(3-Hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazin-3-yl]-methanone, 5a
[0428] Using an adaptation of Procedure 4, and substituting
3-hydroxypyrrolidine for diethylamine, the title compound
(3-hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazin-3-yl]-methanone, 5a was obtained as a TFA salt. MS
m/z (MH.sup.+) 420.1.
##STR00020##
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl-phenethyl-amide
[0429] Using an adaptation of Procedure 4, and substituting
N-methyl-N-phenethylamine for diethylamine, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl-phenethyl-amide, 6a was obtained as a TFA salt. MS m/z
(MH.sup.+) 468.3.
Example B
##STR00021## ##STR00022##
[0430] Procedure 5
Endo-3-(2-Hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b and
Exo-3-(2-Hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 2b
[0431] To a solution of 2-aminophenol (5.0 g; 45.82 mmol) and
3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
(15.5 g; 68.8 mmol) in dichloroethane (200 mL) was added acetic
acid (2.62 mL; 45.77 mmol). The mixture was stirred at rt for 1 h
and sodium triacetoxyborohydride (11.6 g; 54.73 mmol) was added in
small portions. The mixture was stirred at rt for 16 h and treated
with H.sub.2O (200 mL). The organic layer was separated, dried over
MgSO.sub.4, filtered, and evaporated. The residue was purified via
column chromatography (eluent gradient: 10 to 30% ethyl acetate in
heptane) to yield 8 g (55%) of
endo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b and 1.5 g (10%) of
exo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b. MS m/z (MH.sup.+) 318.9.
Procedure 6
Endo-3-(3-Cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b
[0432] To a solution of 4-fluoro-3-nitrobenzonitrile (0.29 g; 1.74
mmol) and
endo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxyli-
c acid tert-butyl ester, 1b (0.55 g; 1.73 mmol) in DMF (6 mL) was
added potassium carbonate (0.48 g; 3.47 mmol). The mixture was
stirred at 170.degree. C. for 30 min. The mixture was allowed to
cool to rt and poured into ice-water 910 mL). The solid was
separated via filtration, washed with water, and dried to yield
0.63 g (86%) of
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b. MS m/z (MH.sup.+) 417.9.The material was
used as such for the next reaction.
Procedure 7
Endo-3-[3-(1H-Tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]octane--
8-carboxylic acid tert-butyl ester, 4b
[0433] To a solution of
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b (1 g; 2.4 mmol) in DMF (20 mL) were added
sodium azide (0.47 g, 7.23 mmol) and ammonium chloride (0.39 g;
7.29 mmol), and the mixture was heated at 120.degree. C. for 16 h.
The mixture was allowed to cool to rt, and filtered. The filtrate
was acidified with 1N hydrochloric acid (10 mL) and extracted with
ethyl acetate (3.times.10 mL). The combined organic layers were
dried over MgSO.sub.4, filtered, and evaporated. The residue was
used as such for the next reaction.
Procedure 8
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazin-
e, 5b
[0434] To a solution of
endo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octan-
e-8-carboxylic acid tert-butyl ester, 4b (2.4 mmol) in dioxane (5
mL) was added a 4N hydrochloric acid solution (5 mL). The mixture
was stirred at rt for 16 h. The mixture was filtered, and the
filtrate was evaporated. The residue was purified via reverse phase
chromatography (eluent gradient: acetonitrile in water containing
0.1% TFA) to yield
crudeendo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phen-
oxazine, 5b as a TFA salt. MS m/z (MH.sup.+) 360.9. The material
was used as such in the next reaction.
Procedure 9
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-
-5-yl)-10H-phenoxazine, 6b
[0435] To a suspension of the HCl salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b (0.2 g; 0.5 mmol) and 2-pyridylcarboxaldehyde (0.071 mL;
0.74 mmol) in dichloroethane (4 mL) was added sodium
triacetoxyborohydride (0.13 g; 0.61 mmol). The mixture was stirred
at rt for 15 h and a saturated NaHCO.sub.3 solution (3 mL). The
organic layer was separated, and the aqueous phase was extracted
with ethyl acetate (5 mL). The combined organic layers were dried
over MgSO.sub.4, filtered, and evaporated. The residue was purified
via reverse phase HPLC (eluent: acetonitrile in water containing
0.1% TFA) to yield 139.8 mg (quant.) of title compound
endo-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazo-
l-5-yl)-10H-phenoxazine, 6b as a TFA salt. MS m/z (MH.sup.+)
452.0.
##STR00023##
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-1-
0H-phenoxazine, 7b
[0436] Using an adaptation of Procedure 9, and substituting
phenylacetaldehyde for 2-pyridyl carboxaldehyde, the title compound
endo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-1-
0H-phenoxazine, 7b was obtained as a TFA salt. MS m/z (MH.sup.+)
464.9.
##STR00024##
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile,
8b
[0437] Using an adaptation of Procedure 9, and substituting
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b for
endo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octan-
e-8-carboxylic acid tert-butyl ester, 4b, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile,
8b was obtained as a TFA salt. MS m/z (MH.sup.+) 317.9.
Example C
##STR00025##
[0438] Procedure 10
Endo-3-[3-(N,N-Diethyl-carbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.-
1]-octane-8-carboxylic acid tert-butyl ester, 1c
[0439] To a solution of methylmagnesium bromide in diethyl ether
(3.0 M, 2.4 mL, 7.2 mmol) under nitrogen was added dropwise a
solution of diethylamine (0.749 mL, 7.19 mmol) in diethyl ether (2
mL). The mixture was heated to reflux for 30 min, cooled to rt, and
a suspension of
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b (1.0 g, 2.4 mmol) was added. The mixture
was stirred at 40.degree. C. for 2 hr and water (10 mL) was added.
The organic layer was separated, and the aqueous layer was further
extracted with chloroform (2.times.10 mL). The combined organic
layers were dried over magnesium sulfate, filtered, and evaporated,
yielding title compound
endo-3-[3-(N,N-diethyl-carbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2-
.1]-octane-8-carboxylic acid tert-butyl ester 1c. MS m/z (MH.sup.+)
491.0.The residue was used as such for the next reaction.
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-10H-phenoxazine-3-carbo-
xamidine, 2c
[0440] Using an adaptation of Procedure 8, and substituting
endo-343-(N,N-Diethyl-carbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.-
1]-octane-8-carboxylic acid tert-butyl ester, 4b for
endo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octan-
e-8-carboxylic acid tert-butyl ester, 4b, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-10H-phenoxazine-3-carb-
oxamidine, 2c was obtained as a TFA salt. MS m/z (MH.sup.+)
390.9.
Endo-N,N-Diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10-
H-phenoxazine-3-carboxamidine, 3c
[0441] Using an adaptation of Procedure 8, and substituting
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-N,N-diethyl-10H-phenoxazine-3-carb-
oxamidine, 2c for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, the title compound
endo-N,N-diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazine-3-carboxamidine, 3c was obtained as a TFA salt. MS
m/z (MH.sup.+) 482.0.
##STR00026##
Endo-N,N-Diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenox-
azine-3-carboxamidine, 4c
[0442] Using an adaptation of Procedure 9, substituting
endo-N,N-diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazine-3-carboxamidine, 3c for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b and phenyl acetaldehyde for 2-pyridyl carboxaldehyde, the
title compound
endo-N,N-diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenoxazine-3-carboxamidine, 4c was obtained as a TFA salt. MS
m/z (MH.sup.+) 495.0.
Example D
##STR00027## ##STR00028##
[0443] Procedure 11
Endo-3-[3-(N-Hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]o-
ctane-8-carboxylic acid tert-butyl ester, 1d and
endo-3-(3-Carbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2d
[0444] To a solution of
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b (1 g; 2.40 mmol) in ethanol (20 mL) were
added ammonium hydroxide hydrochloride (0.5 g; 7.19 mmol) and
potassium carbonate (0.66 g; 4.78 mmol), and the mixture was heated
to reflux for 16 h. The mixture was allowed to cool to rt, water
(20 mL) was added, and the mixture was extracted with ethyl acetate
(2.times.20 mL). The combined organic layers were dried over
MgSO.sub.4, filtered, and evaporated, yielding a .about.2:1 mixture
of title compounds
endo-343-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]o-
ctane-8-carboxylic acid tert-butyl ester, 1d and
endo-3-(3-carbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2d. The crude mixture was used as such
in the next reaction. 1d: MS m/z (MH.sup.+) 451.2, 2d: MS m/z
(MH.sup.+) 458.3.
Procedure 12
Endo-3-[3-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxazin-10-yl]-8-az-
a-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 3d
[0445] To a solution of the 2:1 mixture of
endo-3-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-
octane-8-carboxylic acid tert-butyl ester, 1d and
endo-3-(3-carbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2d (2.33 mmol) in dioxane (20 mL) was
added 1,1'-carbonyldiimidazole (0.57 g; 3.52 mmol), and the mixture
was stirred at 110.degree. C. for 4 h. The mixture was allowed to
cool to rt, and the solution containing a crude mixture of
endo-3-[3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxazin-10-yl]-8-a-
za-bicyclo[3.2.1]-octane-8-carboxylic acid tert-butyl ester, 3d (MS
m/z (MH.sup.+) 477.1)and
endo-3-(3-carbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2d was used as such in the next
reaction.
Endo-3-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]o-
xadiazol-5-one, 4d and
endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid amide, 5d
[0446] Using an adaptation of Procedure 8, and substituting a
mixture of
endo-3-[3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxazin-10-yl]-8-a-
za-bicyclo[3.2.1]-octane-8-carboxylic acid tert-butyl ester, 3d and
endo-3-(3-carbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2d for
endo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octan-
e-8-carboxylic acid tert-butyl ester, 4b, the title compounds
endo-3-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]-
oxadiazol-5-one, 4d and
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid amide, 5d were obtained as TFA salts. 4d: MS m/z (MH.sup.+)
377.0; 5d: MS m/z (MH.sup.+) 335.9.
Endo-3-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxa-
zin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 6d
[0447] Using an adaptation of Procedure 9, and substituting
endo-3-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]-
oxadiazol-5-one, 4d for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, the title compound
endo-3-[10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenox-
azin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 6d was obtained as a TFA
salt. MS m/z (MH.sup.+) 467.9.
##STR00029##
Endo-3-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl-
]-4H-[1,2,4]oxadiazol-5-one, 7d
[0448] Using an adaptation of Procedure 9, and substituting
endo-3-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]-
oxadiazol-5-one, 4d for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, and phenyl acetaldehyde for 2-pyridyl carboxaldehyde, the
title compound
endo-3-[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenox-
azin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 7d was obtained as a TFA salt
MS m/z (MH.sup.+) 480.9.
Example E
##STR00030## ##STR00031##
[0449] Procedure 13
1-Fluoro-3-methoxy-2-nitrobenzene, 1e
[0450] To a solution of 2,6-difluoronitrobenzene (5 g, 32 mmol) in
methanol (50 mL) was added potassium hydroxide (1.8 g, 32.5 mmol),
and the mixture was heated to reflux for 3 hr. Water was added, and
the mixture was extracted with dichloromethane. The organic layer
was separated, dried, filtered, and evaporated to yield 5.1 g (95%)
of 1-fluoro-3-methoxy-2-nitrobenzene, 1e. MS m/z (MH.sup.+)
172.
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1
]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2e
[0451] Using an adaptation of Procedure 2, and substituting
1-fluoro-3-methoxy-2-nitrobenzene, 1e for
4-fluoro-3-nitrobenzonitrile, the title compound
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid methyl ester, 2e was obtained as a TFA salt and as a
mixture of endo and exo isomers. MS m/z (MH.sup.+) 395.
Procedure 14
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-car-
boxylic acid, 3e
[0452] To a solution of the TFA salt of
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid methyl ester, 2e (270 mg, 0.7 mmol) in dioxane (15
mL) was added sodium hydroxide (31 mg, 0.77 mmol) for
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid methyl ester, 2a, the title compound
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid, 3e was obtained as a mixture of endo and exo
isomers. MS m/z (MH.sup.+) 381.
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 4e
[0453] Using an adaptation of Procedure 4, and substituting
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid, 3e for
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid, 3a, N,N-diisopropyl-N-ethylamine for triethylamine and HATU
for HBTU, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 4e was obtained as a TFA salt and as a mixture
of endo and exo isomers. MS m/z (MH.sup.+) 436.
Procedure 15
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 5e
[0454] To a solution of the TFA salt of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 4e (110 mg, 0.25 mmol) in methylene chloride (10
mL) was added 1-chloroethyl chloroformate (0.58 mL, 0.75 mmol). The
mixture was heated to reflux for 2 h. The mixture was evaporated,
dissolved in methanol (5 mL), and heated for 2 h at reflux. Water
was added, and the solution was extracted with methylene chloride.
The organic phase was separated, evaporated, and purified via
reverse phase HPLC to yield 69 mg (44.8%) of title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 5e, as a TFA salt. MS m/z=422 (M+1).
6-Methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3--
carboxylic acid diethylamide, 6e
[0455] Using an adaptation of Procedure 9, and substituting
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 5e for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, and phenyl acetaldehyde for 2-pyridylcarboxaldehyde, the
title compound
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phen-
oxazine-3-carboxylic acid diethylamide, 6e was obtained as a TFA
salt and as a mixture of endo and exo isomers. MS m/z=526
(M+1).
Procedure 16
6-Hydroxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3--
carboxylic acid diethylamide, 7e
[0456] To a solution of the TFA salt of
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e (55 mg, 0.086 mmol) in
1,2-dichloromethane (5 mL) at 0.degree. C. was added a 1M solution
of BBr.sub.3 (0.43 mL, 0.43 mmol). The mixture was allowed to stir
for 2 h at rt. A saturated NaHCO.sub.3 solution was added, and the
organic phase was separated. The aqueous phase was extracted with
methylene chloride, and the combined organic phases were dried,
filtered, and evaporated. The residue was purified via reverse
phase HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield 23
mg (42.8%) of title compound
6-hydroxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 7e as a TFA salt and as a mixture of
endo and exo isomers. MS m/z=512 (M+1).
##STR00032##
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid diethylamide, 8e
[0457] Using an adaptation of Procedure 16, and substituting the
TFA salt of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxyli-
c acid diethylamide, 4e for TFA salt of
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e, the title compound
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxylic acid diethylamide, 8e was obtained as a TFA salt and as a
mixture of endo and exo isomers after reverse phase chromatography
(eluent gradient: acetonitrile in water containing 0.1% TFA). MS
m/z (MH.sup.+) 422.
Example F
##STR00033##
[0458] 2-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-phenol,
1f
[0459] Using an adaptation of Procedure 5, and substituting
8-methyl-8-aza-bicyclo[3.2.1]-octan-3-one for
3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl
ester, the title compound
2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-phenol, 1f was
obtained as a TFA salt and as a mixture of endo and exo isomers
after reverse phase chromatography (eluent gradient: acetonitrile
in water containing 0.1% TFA). MS m/z (MH.sup.+) 232.9.
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile,
2f
[0460] Using an adaptation of Procedure 6, and substituting the TFA
salt of 2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-phenol, 1f
for
3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile-
, 2f was obtained as a mixture of endo and exo isomers. MS m/z
(MH.sup.+) 332.0.
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenox-
azine, 3f
[0461] Using an adaptation of Procedure 7, and substituting
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile-
, 2f for
3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxy-
lic acid tert-butyl ester, 2b, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-pheno-
xazine, 3f was obtained as a TFA salt and as a mixture of endo and
exo isomers after reverse phase chromatography (eluent gradient:
acetonitrile in water containing 0.1% TFA). MS m/z (MH.sup.+)
375.1.
Example G
##STR00034##
[0462]
N,N-Diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxaz-
ine-3-carboxamidine, 1g
[0463] Using an adaptation of Procedure 10, and substituting
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile-
, 2f for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-ca-
rboxylic acid tert-butyl ester, 3b, the title compound
N,N-diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3--
carboxamidine, 1g was obtained as a TFA salt and as a mixture of
endo and exo isomers after reverse phase chromatography (eluent
gradient: acetonitrile in water containing 0.1% TFA). MS m/z
(MH.sup.+) 405.3.
Example H
##STR00035##
[0464]
N-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxamidine, 1h
[0465] Using an adaptation of Procedure 11, and substituting
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile-
, 2f for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-ca-
rboxylic acid tert-butyl ester, 3b, the title compound
N-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxamidine, 1h was obtained. MS m/z (MH.sup.+) 365.0.
Procedure 17
3-[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2-
,4]oxadiazol-5-one, 2h
[0466] To a solution of
N-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rboxamidine, 1h (0.66 g; 1.81 mmol) in dioxane (20 mL) was added
1,1'-carbonyldiimidazole (0.44 g; 2.71 mmol), and the mixture was
stirred at 110.degree. C. for 4 h. The mixture was allowed to cool
to rt, and the solvent was evaporated. The residue was purified via
reverse phase HPLC (eluent gradient: 20 to 45% CH.sub.3CN in
H.sub.2O containing 0.1% TFA) to yield 161 mg (17.6%) of title
compound
3-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,-
2,4]oxadiazol-5-one, 2 h as a TFA salt. MS m/z (MH.sup.+)
390.9.
Example I
##STR00036## ##STR00037##
[0467] Procedure 18
Spiro Compound, 1i
[0468] A mixture of 2-aminothiophenol (4.3 mL, 39.9 mmol) and
tropinone (5.6 g, 39.9 mmol) was allowed to stir and sit for 16 h
at rt. The mixture was placed under vacuum (<0.3 mm Hg) for 6 h.
HPLC-MS analysis revealed .about.60% conversion to desired
compound, 1i. The material was used as such for the next
reaction.
Procedure 19
[2-(4-Bromo-2-nitrophenylsulfanyl)-phenyl]-(8-methyl-8-aza-bicyclo[3.2.1]o-
ct-3-yl)-amine, 2i
[0469] To the mixture obtained from the previous reaction
(Procedure 18) was added THF (20 mL), and the mixture was cooled to
-78.degree. C. A 1M solution of lithium aluminum hydride in diethyl
ether (60 mL, 60 mmol) was added in portions. The cooling bath was
removed. More THF (60 mL) and 10 mL of the 1M solution of lithium
aluminum hydride were added. The mixture was stirred at rt for 90
min, cooled to -78.degree. C., and treated with water (2.6 mL). The
cooling bath was removed, and the mixture was allowed to warm to
rt. A 1N NaOH solution (10.6 mL) was added, and the mixture was
allowed to stir for 15 min. MgSO.sub.4 (1 g) and THF (40 mL) were
added, and the mixite was filtered. To the filtrate was added
2-fluoro-5-bromo-nitrobenzene (5.4 mL, 43.8 mmol), and the mixture
was stirred for 15 min. The reaction mixture was filtered, and the
solid was washed with THF (3.times.20 mL) and ethyl acetate
(4.times.20 mL). The combined filtrates were evaporated, and the
residue was purified via flash column chromatography (eluent
gradient: 20% EtOAc containing 1% Et.sub.3N in heptane to 20% MeOH
containing 1% Et.sub.3N in EtOAc), yielding 10 g (55.9%) of title
compound
[2-(4-bromo-2-nitrophenylsulfanyl)-phenyl]-(8-methyl-8-aza-bicyclo[3.2.1]-
oct-3-yl)-amine, 2i as a mixture of endo and exo isomers.
Procedure 20
3-Bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i
[0470] To a solution of
[2-(4-bromo-2-nitrophenylsulfanyl)-phenyl]-(8-methyl-8-aza-bicyclo[3.2.1]-
oct-3-yl)-amine, 2i (9.7 g, 21.6 mmol) in DMSO (220 mL) was added
potassium carbonate (3.3 g, 23.8 mmol). The mixture was heated
under a N.sub.2 atmosphere to 170.degree. C. for 45 min. The
mixture was allowed to cool to rt, diluted with H.sub.2O (250 mL),
and extracted with EtOAc (4.times.100 mL). The organic phase was
dried over Na.sub.2SO.sub.4, filtered, and evaporated. The residue
was purified via flash column chromatography (eluent gradient: 1%
Et.sub.3N in EtOAc to 30% MeOH in EtOAc containing 1% Et.sub.3N),
yielding 1.9 g (21.9%) of title compound
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i as a mixture of endo and exo isomers. MS m/z (MH.sup.+)
401.1/403.1.
Procedure 21
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-10H-phenothiazine, 4i
[0471] To a solution of
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i (1.0 g, 2.49 mmol) in 1,2-dichloroethane (15 mL) were added
1-chloroethyl chloroformate (807 .mu.L, 7.5 mmol) and
N,N-diisopropyl-N-ethylamine (1.4 mL, 7.97 mmol). The mixture was
heated to reflux for 2.5 h, allowed to cool to rt, and evaporated.
The mixture was evaporated and the residue was dissolved dissolved
in methanol (15 mL) and heated to reflux for 1 h. After work-up,
the residue was purified via flash column chromatography (eluent
gradient: 0 to 30% MeOH in EtOAc containing 1% triethylamine) to
yield 150 mg of recovered starting material 3i and 382 mg (66%) of
title compound 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i as a
mixture of endo and exo isomers. MS m/z (MH.sup.+) 387.1/389.1.
Procedure 22
3-Bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothia-
zine, 5i
[0472] To a solution of
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i (11.2 mg; 0.029
mmol) and 3-furyl carboxaldehyde (8.4 mg; 0.087 mmol) in
dichloroethane (120 .mu.L) was added acetic acid (5 .mu.L) and a
solution of sodium triacetoxyborohydride (12 mg, 0.057 mmol) in DMF
(100.mu.). The mixture was stirred at rt for 18 h, quenched with
water (50 .mu.L), and lyophilized. The thus obtained crude
3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine, 5i as a mixture of endo and exo isomers was used as such for
the next reaction.
Procedure 23
10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-ph-
enothiazine, 6i
[0473] A mixture of
3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine, 5i (13.5 mg, 0.029 mmol), 3-pyridyl boronic acid (10.7 mg,
0.087 mmol), potassium carbonate (12 mg, 0.087 mmol) and
Pd(PPh.sub.3).sub.4 (3 mg, 2.5 .mu.mol) in NMP (300 .mu.L) and
H.sub.2O (100 .mu.L) was heated to 160.degree. C. for 10 min in a
microwave. The mixture was absorbed onto a 1 g SPE cartridge and
eluted (eluent: 10% methanol in ethyl acetate containing 1%
triethylamine). The eluent (.about.15 mL) was collected and
evaporated. The residue was purified via reverse phase HPLC
(eluent: acetonitrile in water containing 0.1% TFA) to yield title
compound
10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-
-yl-10H-phenothiazine, 6i as a TFA salt and as a mixture of endo
and exo isomers. MS m/z (MH.sup.+) 466.2.
##STR00038##
N-{2-[10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiaz-
in-3-yl]-phenyl}-acetamide, 7i
[0474] Using an adaptation of the method described in Procedure 23,
substituting 2-acetylaminophenyl boronic acid for 3-pyridyl boronic
acid, the title compound
N-{2-[10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiaz-
in-3-yl]-phenyl}-acetamide, 7i was obtained as a TFA salt and as a
mixture of endo and exo isomers. MS m/z (MH.sup.+) 522.2.
##STR00039##
10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-3-yl--
10H-phenothiazine, 8i
[0475] Using an adaptation of the methods described in Procedures
22 and 23, substituting 3-methyl-but-2-enal for 3-furyl
carboxaldehyde in Procedure 22, the title compound
10-[8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-3-yl--
10H-phenothiazine, 8i was obtained as a TFA salt and as a mixture
of endo and exo isomers. MS m/z (MH.sup.+) 454.3.
##STR00040##
3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine, 9i
[0476] Using an adaptation of the methods described in Procedures
22 and 23, substituting 2-pyridyl carboxaldehyde for 3-furyl
carboxaldehyde in Procedure 22, the title compound
3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine, 9i was obtained as a TFA salt and as a mixture of
endo and exo isomers. MS m/z (MH.sup.+) 477.2.
##STR00041##
10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-4-yl--
10H-phenothiazine, 10i
[0477] Using an adaptation of the methods described in Procedures
22 and 23, substituting 3-methyl-but-2-enal for 3-furyl
carboxaldehyde in Procedure 22, and 4-pyridyl boronic acid for
3-pyridyl boronic acid in Procedure 23, the title compound
10-[8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-3-pyridin-4-yl--
10H-phenothiazine, 10i was obtained as a TFA salt and as a mixture
of endo and exo isomers. MS m/z (MH.sup.+) 454.3.
##STR00042##
3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine, 11i
[0478] Using an adaptation of the methods described in Procedures
22 and 23, substituting 2-pyridyl carboxaldehyde for 3-furyl
carboxaldehyde in Procedure 22, and 4-pyridyl boronic acid for
3-pyridyl boronic acid in Procedure 23, the title compound
3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenothiazine, 11i was obtained as a TFA salt and as a mixture of
endo and exo isomers. MS m/z (MH.sup.+) 477.3.
##STR00043##
3-Pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10-
H-phenothiazine, 12i
[0479] Using an adaptation of the methods described in Procedures
22 and 23, substituting 2-thiophene carboxaldehyde for 3-furyl
carboxaldehyde in Procedure 22, and 4-pyridyl boronic acid for
3-pyridyl boronic acid in Procedure 23, the title compound
3-pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10-
H-phenothiazine, 12i was obtained as a TFA salt and as a mixture of
endo and exo isomers. MS m/z (MH.sup.+) 482.2.
##STR00044##
N-{2-[10-(8-Allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-ph-
enyl}-acetamide, 13i
[0480] Using an adaptation of the methods described in Procedures
22 and 23, substituting propenal for 3-furyl carboxaldehyde in
Procedure 22, and 2-acetylaminophenyl boronic acid for 3-pyridyl
boronic acid in Procedure 23, the title compound
N-{2-[10-(8-allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-ph-
enyl}-acetamide, 13i was obtained as a TFA salt and as a mixture of
endo and exo isomers.
##STR00045##
N-{2-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl-
]-phenyl}-acetamide, 14i
[0481] Using an adaptation of the methods described in Procedures
22 and 23, substituting phenyl acetaldehyde for 3-furyl
carboxaldehyde in Procedure 22, and 2-acetylaminophenyl boronic
acid for 3-pyridyl boronic acid in Procedure 23, the title compound
N-{2-[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl-
]-phenyl}-acetamide, 14i was obtained as a TFA salt and as a
mixture of endo and exo isomers. MS m/z (MH.sup.+) 546.3.
##STR00046##
N-(2-{10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-ph-
enothiazin-3-yl}-phenyl)-acetamide, 15i
[0482] Using an adaptation of the methods described in Procedures
22 and 23, substituting 1H-imidazole-2-carboxaldehyde for 3-furyl
carboxaldehyde in Procedure 22, and 2-acetylaminophenyl boronic
acid for 3-pyridyl boronic acid in Procedure 23, the title compound
N-(2-{10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-ph-
enothiazin-3-yl}-phenyl)-acetamide, 15i was obtained as a TFA salt
and as a mixture of endo and exo isomers. MS m/z (MH.sup.+)
522.3.
##STR00047##
N-{2-[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-p-
henyl}-acetamide, 16i
[0483] Using an adaptation of the method described in Procedure 23,
substituting
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i for
3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phen-
othiazine, 5i and 2-acetylaminophenyl boronic acid for 3-pyridyl
boronic acid, the title compound
N-{2-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-p-
henyl}-acetamide, 16i was obtained as a TFA salt and as a mixture
of endo and exo isomers. MS m/z (MH.sup.+) 456.2.
##STR00048##
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenothiazine,
17i
[0484] Using an adaptation of the method described in Procedure 23,
substituting 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i for
3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine, 5i, the title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenothiazine,
17i was obtained as a TFA salt and as a mixture of endo and exo
isomers. MS m/z (MH.sup.+) 386.2.
##STR00049##
N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-phenyl}-ac-
etamide, 18i
[0485] Using an adaptation of the method described in Procedure 23,
substituting
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-10H-phenothiazine, 4i for
3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-p-
henothiazine, 5i and 2-acetylaminophenyl boronic acid for 3-pyridyl
boronic acid, the title compound
N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-phenyl}-ac-
etamide, 18i was obtained as a TFA salt and as a mixture of endo
and exo isomers. MS m/z (MH.sup.+) 442.2.
##STR00050##
10-(8-Allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenothiazin-
e, 19i
[0486] Using an adaptation of the methods described in Procedures
22 and 23, substituting 2-propenal for 3-furyl carboxaldehyde in
Procedure 22, the title compound
10-(8-allyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenothiazin-
e, 19i was obtained as a TFA salt and as a mixture of endo and exo
isomers. MS m/z (M+18+H) 444.2.
##STR00051## ##STR00052##
Endo-3-(4-Chloro-2-hydroxyphenylamino)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 1j and
exo-3-(4-chloro-2-hydroxyphenyl-amino)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 2j
[0487] Using an adaptation of the method described in Procedure 1,
substituting 2-amino-5-chlorophenol for 4-amino-3-hydroxybenzoic
acid methyl ester and 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one,
a 3:1 mixture of title compounds
endo-3-(4-chloro-2-hydroxyphenylamino)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 1j and
exo-3-(4-chloro-2-hydroxyphenyl-amino)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 2j was obtained. Compounds 1j and 2j
were separated via flash column chromatography (eluent gradient: 3%
to 65% EtOAc in hexane), yielding 70% of endo isomer 1j (first
eluting isomer; and 19% of exo isomer 2j (second eluting
isomer)
Endo-3-(3-Chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3j
[0488] Using an adaptation of the method described in Procedure 2,
substituting
endo-3-(4-chloro-2-hydroxyphenylamino)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 1j for the TFA salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a, the title compound
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3j was obtained.
Procedure 24
Endo-3-(3-Pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 4j
[0489] To a mixture of 3-pyridyl boronic acid (70.1 mg, 0.57 mmol),
Cp.sub.2Fe(P-tBu.sub.2).sub.2PdCl.sub.2 (62 mg, 0.095 mmol),
potassium carbonate (88 mg, 0.63 mmol) was added a solution of
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3j (135 mg, 0.317 mmol) in dioxane (3 mL,
degassed with argon for 5 min prior to use). The mixture was heated
to 120.degree. C. for 30 min in a microwave (300 W). The mixture
was allowed to cool to rt, water and ethyl acetate were added. The
organic layer was separated, dried over MgSO4, filtered, and
evaporated to yield 195 mg of crude title compound
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oct-
ane-8-carboxylic acid tert-butyl ester, 4j. The material was used
as such for the next reaction.
Procedure 25
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine,
5j
[0490] The crude
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, obtained from the previous
reaction, was treated with TFA (3 mL), and the mixture was stirred
for 30 min at rt. The TFA was removed under a nitrogen stream, and
the residue was purified via reverse phase HPLC (eluent gradient:
10% to 30% CH.sub.3CN in water containing 0.1% TFA). The desired
fractions were combined, lyophilized, and dissolved in diethyl
ether. The solution was washed with a saturated NaHCO.sub.3
solution. The aqueous phase was washed with diethyl ether, and the
combined organic phases were dried over MgSO.sub.4, filtered, and
evaporated to yield 58 mg (43% for 2 steps) of title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine,
5j. MS m/z (MH.sup.+) 370.2.
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phen-
oxazine, 6j
[0491] Using an adaptation of the method described in Procedure 9,
substituting
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine,
5j for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and phenyl acetaldehyde for 2-pyridylcarboxaldehyde, the title
compound
endo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-y-
l-10H-phenoxazine, 6j was obtained as a TFA salt. MS m/z (MH.sup.+)
474.2.
##STR00053##
Endo-3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazine, 7j
[0492] Using an adaptation of the method described in Procedure 9,
substituting
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine,
5j for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and 2-pyridyl carboxaldehyde for 2-pyridylcarboxaldehyde, the
title compound
endo-3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1-
]oct-3-yl)-10H-phenoxazine, 7j was obtained as a TFA salt. MS m/z
(MH.sup.+) 461.2.
##STR00054##
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl--
10H-phenoxazine, 8j
[0493] Using an adaptation of the method described in Procedure 9,
substituting
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine,
5j for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and 3-furaldehyde for 2-pyridylcarboxaldehyde, the title
compound
endo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl--
10H-phenoxazine, 8j was obtained as a TFA salt. MS m/z (MH.sup.+)
450.2.
##STR00055##
Endo-3-Pyridin-3-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine, 9j
[0494] Using an adaptation of the method described in Procedure 9,
substituting
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-phenoxazine,
5j for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and 2-thiophene carboxaldehyde for 2-pyridylcarboxaldehyde, the
title compound
endo-3-pyridin-3-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine, 9j was obtained as a TFA salt. MS m/z
(MH.sup.+) 466.2.
##STR00056##
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-10H-phenoxazine,
10j
[0495] Using an adaptation of the method described in Procedure 25,
substituting endo-3-(3-chloro-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1
]octane-8-carboxylic acid tert-butyl ester, 3j for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, the title compound
endo-10-(8-aza-bicyclo[3.2.1]-oct-3-yl)-3-chloro-10H-phenoxazine,
10j was obtained as a TFA salt after reverse phase HPLC
purification (eluent: CH.sub.3CN in water containing 0.1% TFA). MS
m/z (MH.sup.+) 327.1.
Example K
##STR00057##
[0496]
Endo-3-(3-Pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-
-8-carboxylic acid tert-butyl ester, 1k
[0497] Using an adaptation of the method described in Procedure 24,
substituting 4-pyridyl boronic acid for 3-pyridyl boronic acid, the
title compound
endo-3-(3-pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oct-
ane-8-carboxylic acid tert-butyl ester, 1k was obtained.
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2k
[0498] Using an adaptation of the method described in Procedure 25,
substituting
endo-3-(3-pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 1k for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]-octane-8-ca-
rboxylic acid tert-butyl ester, 4j, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2k was obtained as a TFA salt after reverse phase HPLC purification
(eluent gradient: 10% to 30% CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 370.2.
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phen-
oxazine, 3k
[0499] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2k for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and phenyl acetaldehyde for 2-pyridyl carboxaldehyde, the title
compound
endo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-y-
l-10H-phenoxazine, 3k was obtained as a TFA salt. MS m/z (MH.sup.+)
474.3.
##STR00058##
Endo-3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazine, 4k
[0500] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2k for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b, the title compound
endo-3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazine, 4k was obtained as a TFA salt. MS m/z (MH.sup.+)
461.3.
##STR00059##
Endo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl--
10H-phenoxazine, 5k
[0501] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2k for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and 3-furaldehyde for 2-pyridylcarboxaldehyde, the title
compound
endo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl--
10H-phenoxazine, 5k was obtained as a TFA salt. MS m/z (MH.sup.+)
450.3.
##STR00060##
Endo-3-Pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-y-
l)-10H-phenoxazine, 6k
[0502] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2k for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and 2-thiophene carboxaldehyde for 2-pyridylcarboxaldehyde, the
title compound
endo-3-pyridin-4-yl-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine, 6k was obtained as a TFA salt. MS m/z
(MH.sup.+) 466.2.
Example L
##STR00061##
[0503]
Exo-3-(3-Chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 1l
[0504] Using an adaptation of the method described in Procedure 2,
substituting
exo-3-(4-chloro-2-hydroxyphenylamino)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2j for the TFA salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a, the title compound
exo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1l was obtained.
Endo-3-(3-Pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 2l
[0505] Using an adaptation of the method described in Procedure 24,
substituting
exo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1l for
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3j, the title compound
3-(3-pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxyl-
ic acid tert-butyl ester, 2l was obtained.
Exo-3-(3-Pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbo-
xylic acid tert-butyl ester, 3l
[0506] Using an adaptation of the method described in Procedure 25,
substituting
exo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 2l for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]-octane-8-ca-
rboxylic acid tert-butyl ester, 4j, the title compound
exo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 3l was obtained as a TFA salt after
reverse phase HPLC purification (eluent gradient: 10% to 30%
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
370.2.
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-10H-pheno-
xazine, 4l
[0507] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
exo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 3l for the HCl salt of
10-(8-aza-bicyclo[3.2.1
]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 4b and phenyl
acetaldehyde for 2-pyridyl carboxaldehyde, the title compound
exo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-
-10H-phenoxazine, 4l was obtained as a TFA salt. MS m/z (MH.sup.+)
474.3.
##STR00062##
Exo-3-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazine, 5l
[0508] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
exo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 3l for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b, the title compound
exo-3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazine, 5l was obtained as a TFA salt. MS m/z (MH.sup.+)
461.3.
##STR00063##
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-1-
0H-phenoxazine, 6l
[0509] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
exo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 3l for the HCl salt of
10-(8-aza-bicyclo[3.2.1
]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 4b and
3-furaldehyde for 2-pyridyl carboxaldehyde, the title compound
exo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-3-yl-1-
0H-phenoxazine, 6l was obtained as a TFA salt. MS m/z (MH.sup.+)
450.2.
##STR00064##
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-10H-phenoxazine,
7l
[0510] Using an adaptation of the method described in Procedure 25,
substituting
exo-3-(3-chloro-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1l for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, the title compound
exo-10-(8-aza-bicyclo[3.2.1]-oct-3-yl)-3-chloro-10H-phenoxazine, 7l
was obtained as a TFA salt after reverse phase HPLC purification
(eluent: CH.sub.3CN in water containing 0.1% TFA). MS m/z
(MH.sup.+) 327.1.
Example M
##STR00065##
[0511]
Exo-3-(3-Pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane--
8-carboxylic acid tert-butyl ester, 1m
[0512] Using an adaptation of the method described in Procedure 24,
substituting 4-pyridyl boronic acid for 3-pyridyl boronic acid, the
title compound
exo-3-(3-pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octa-
ne-8-carboxylic acid tert-butyl ester, 1m was obtained.
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2m
[0513] Using an adaptation of the method described in Procedure 25,
substituting
exo-3-(3-pyridin-4-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 1l for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]-octane-8-ca-
rboxylic acid tert-butyl ester, 4j, the title compound
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2m was obtained as a TFA salt after reverse phase HPLC purification
(eluent gradient: 10% to 30% CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 370.2.
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-pheno-
xazine, 3m
[0514] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2m for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and phenyl acetaldehyde for 2-pyridyl carboxaldehyde, the title
compound
exo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-
-10H-phenoxazine, 3m was obtained as a TFA salt. MS m/z (MH.sup.+)
474.3.
##STR00066##
Exo-3-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazine, 4m
[0515] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2m for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b, the title compound
exo-3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazine, 4m was obtained as a TFA salt. MS m/z (MH.sup.+)
461.2.
##STR00067##
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-1-
0H-phenoxazine, 5m
[0516] Using an adaptation of the method described in Procedure 9,
substituting the TFA salt of
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-10H-phenoxazine,
2m for the HCl salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
4b and 3-furaldehyde for 2-pyridyl carboxaldehyde, the title
compound
exo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4-yl-1-
0H-phenoxazine, 5m was obtained as a TFA salt. MS m/z (MH.sup.+)
450.2.
Example N
##STR00068##
[0517] Exo-
3-(3-Cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1n
[0518] Using an adaptation of the method described in Procedure 6,
substituting
exo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 2b for
endo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b, the title compound
exo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1n was obtained. MS m/z (MH.sup.+)
439.9.
Exo-343-(1H-Tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]octane-8--
carboxylic acid tert-butyl ester, 2n
[0519] Using an adaptation of the method described in Procedure 7,
substituting
exo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1n for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b, the title compound
exo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]octane--
8-carboxylic acid tert-butyl ester, 2n was obtained. MS m/z
(MH.sup.+) 460.9.
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine-
, 3n
[0520] Using an adaptation of the method described in Procedure 8,
substituting
exo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octane-
-8-carboxylic acid tert-butyl ester, 2n for
endo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octan-
e-8-carboxylic acid tert-butyl ester, 4b, the title compound
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazin-
e, 3n was obtained as a TFA salt after purification via reverse
phase HPLC (eluent: CH.sub.3CN in water containing 0.1% TFA). MS
m/z (MH.sup.+) 360.9.
##STR00069##
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile,
4n
[0521] Using an adaptation of the method described in Procedure 25,
substituting
exo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1n for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, and using a 1:1 solution of
TFA;CH.sub.2Cl.sub.2 instead of neat TFA, the title compound
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbonitrile,
4n was obtained as a TFA salt after reverse phase HPLC purification
(eluent gradient: 20% to 45% CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 317.9.
Example O
##STR00070##
[0522]
Exo-3-[3-(N-Hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3-
.2.1]octane-8-carboxylic acid tert-butyl ester, 1o
[0523] Using an adaptation of the method described in Procedure 11,
substituting
exo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1n for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b, the title compound
exo-3-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]o-
ctane-8-carboxylic acid tert-butyl ester, 1o was obtained. MS m/z
(MH.sup.+) 450.9.
Exo-3-[3-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxazin-10-yl]-8-aza-
-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 2o
[0524] Using an adaptation of the method described in Procedure 12,
substituting
exo-3-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]o-
ctane-8-carboxylic acid tert-butyl ester, 1o for the mixture of
endo-3-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-
octane-8-carboxylic acid tert-butyl ester, 1d and
endo-3-(3-carbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 2d, the title compound
exo-3-[3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxazin-10-yl]-8-az-
a-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 2o was
obtained.
Exo-3-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]ox-
adiazol-5-one, 3o
[0525] Using an adaptation of Procedure 8, and substituting
exo-3-[3-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxazin-10-yl]-8-az-
a-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 2o for
endo-3-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]-octan-
e-8-carboxylic acid tert-butyl ester, 4b, the title compound
exo-3-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]o-
xadiazol-5-one, 3o was obtained as TFA salt after purification via
reverse phase HPLC (eluent gradient: 20% to 45% CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 376.8.
Example P
##STR00071##
[0526]
3-Methoxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitri-
le, 1p
[0527] Using an adaptation of Procedure 2, substituting
8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine for the TFA salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a, 1-fluoro-3-methoxy-2-nitrobenzene, 1e for
2-fluoronitrobenzene, and cesium carbonate for potassium carbonate,
the title compound
3-methoxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile,
1p was obtained as TFA salt and as a mixture of endo and exo
isomers after purification via reverse phase HPLC (eluent gradient:
20% to 45% CH.sub.3CN in water containing 0.1% TFA). MS m/z=272
(M+1).
3-Hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile,
2p
[0528] Using an adaptation of Procedure 13, substituting the TFA
salt of
3-methoxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile,
1p for the TFA salt of
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e, the title compound
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile,
2p was obtained as TFA salt and as a mixture of endo and exo
isomers after purification via reverse phase HPLC (eluent gradient:
20% to 45% CH.sub.3CN in water containing 0.1% TFA). MS m/z=258
(M+1).
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-car-
bonitrile, 3p
[0529] Using an adaptation of Procedure 2, substituting the TFA
salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzonitrile,
2p for the TFA salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a, and 1-fluoro-3-methoxy-2-nitrobenzene, 1e
for 2-fluoronitrobenzene, the title compound
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rbonitrile, 3p was obtained as TFA salt and as a mixture of endo
and exo isomers after purification via reverse phase HPLC (eluent
gradient: 20% to 45% CH.sub.3CN in water containing 0.1% TFA). MS
m/z=362 (M+1).
6-Hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-car-
bonitrile, 4p
[0530] Using an adaptation of Procedure 13, substituting the TFA
salt of
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rbonitrile, 3p for the TFA salt of
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e, the title compound
6-hydroxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-ca-
rbonitrile, 4p was obtained as TFA salt and as a mixture of endo
and exo isomers after purification via reverse phase HPLC (eluent
gradient: 20% to 45% CH.sub.3CN in water containing 0.1% TFA). MS
m/z=348 (M+1).
Example Q
##STR00072##
[0531] Procedure 26
[10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-y-
l]-pyrrolidin-1-yl-methanone, 1q
[0532] To a solution of a mixture of endo and exo isomers of
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i (15 mg, 0.04 mmol)
in dichloroethane (0.4 mL) were added 3-furaldehyde (10 .mu.L, 0.12
mmol), acetic acid (5 .mu.L) and sodium triacetoxy-borohydride (17
mg, 0.08 mmol). The mixture was allowed to stir at rt for 16 h, and
quenched with a 2N NaOH solution (200 .mu.L). The mixture was
absorbed onto a 1 g SPE cartridge and eluted (eluent: 10% methanol
in ethyl acetate containing 1% triethylamine). The eluent
(.about.15 mL) was collected and evaporated. The residue was
dissolved in THF (0.4 mL), and pyrrolidine (19 .mu.L, 0.15 mmol),
Mo(CO).sub.6 (16 mg, 0.06 mmol), Herrmann's catalyst (6 mg, 0.006
mmol), and DBU (27 .mu.L, 0.18 mmol) were added. The mixture was
irradiated in a microwave oven at 150.degree. C. for 15 min. The
mixture was evaporated, and the residue was purified via reverse
phase HPLC (eluent gradient: CH.sub.3CN in water containing 0.1%
TFA) to yield
[10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3--
yl]-pyrrolidin-1-yl-methanone, 1q as a TFA salt and as a mixture of
endo and exo isomers. MS m/z (MH.sup.+) 486.2.
##STR00073##
[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-pyr-
rolidin-1-yl-methanone, 2q
[0533] Using an adaptation of Procedure 26, substituting phenyl
acetaldehyde for 3-furaldehyde, the title compound
[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-pyr-
rolidin-1-yl-methanone, 2q was obtained as TFA salt and as a
mixture of endo and exo isomers after purification via reverse
phase HPLC (eluent gradient: 20% to 45% CH.sub.3CN in water
containing 0.1% TFA). MS m/z=510.3 (M+1).
##STR00074##
{10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenothiaz-
in-3-yl}-pyrrolidin-1-yl-methanone, 3q
[0534] Using an adaptation of Procedure 26, substituting
3-methyl-but-2-enal for 3-furaldehyde, the title compound
{10-[8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenothiaz-
in-3-yl}-pyrrolidin-1-yl-methanone, 3q was obtained as TFA salt and
as a mixture of endo and exo isomers after purification via reverse
phase HPLC (eluent gradient: 20% to 45% CH.sub.3CN in water
containing 0.1% TFA). MS m/z=474.2 (M+1).
##STR00075##
[10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3--
yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone, 4q
[0535] Using an adaptation of Procedure 26, substituting
3-hydroxypyrrolidine for pyrrolidine, the title compound
[10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3--
yl]-(3-hydroxy-pyrrolidin-1-yl)-methanone, 4q was obtained as TFA
salt and as a mixture of endo and exo isomers after purification
via reverse phase HPLC (eluent gradient: 20% to 45% CH.sub.3CN in
water containing 0.1% TFA). MS m/z=502.2 (M+1).
##STR00076##
(3-Hydroxy-pyrrolidin-1-yl)-[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenothiazin-3-yl]-methanone, 5q
[0536] Using an adaptation of Procedure 26, substituting phenyl
acetaldehyde for 3-furaldehyde and 3-hydroxypyrrolidine for
pyrrolidine, the title compound
(3-hydroxy-pyrrolidin-1-yl)-[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenothiazin-3-yl]-methanone, 5q was obtained as TFA salt and
as a mixture of endo and exo isomers after purification via reverse
phase HPLC (eluent gradient: 20% to 45% CH.sub.3CN in water
containing 0.1% TFA). MS m/z=526.2 (M+1).
##STR00077##
{10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenothiaz-
in-3-yl}-(3-methyl-pyrrolidin-1-yl)-methanone, 6q
[0537] Using an adaptation of Procedure 26, substituting
3-methyl-but-2-enal for 3-furaldehyde and 3-hydroxypyrrolidine for
pyrrolidine, the title compound
{10-[8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenothiaz-
in-3-yl}-(3-methyl-pyrrolidin-1-yl)-methanone, 6q was obtained as
TFA salt and as a mixture of endo and exo isomers after
purification via reverse phase HPLC (eluent gradient: 20% to 45%
CH.sub.3CN in water containing 0.1% TFA). MS m/z=490.2 (M+1).
Example R
##STR00078##
[0538] Procedure 27
[10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-pyrroli-
din-1-yl-methanone, 1r
[0539] To a solution of
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i (15 mg, 0.04 mmol) in THF (0.3 mL) was added pyrrolidine (12
.mu.L, 0.15 mmol), Mo(CO).sub.6 (16 mg, 0.06 mmol), Herrmann's
catalyst (6 mg, 0.006 mmol), and DBU (27 .mu.L, 0.18 mmol), and the
mixture was irradiated in a microwave oven at 150.degree. C. for 15
min. The mixture was evaporated, and the residue was purified via
reverse phase HPLC (eluent gradient: CH.sub.3CN in water containing
0.1% TFA) to yield
[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazin-3-yl]-pyrrol-
idin-1-yl-methanone, 1r as a TFA salt and a mixture of endo and exo
isomers. MS m/z (MH.sup.+) 420.2.
##STR00079##
(3-Hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenothiazin-3-yl]-methanone, 2r
[0540] Using an adaptation of Procedure 27, substituting
3-hydroxypyrrolidine for pyrrolidine, the title compound
(3-hydroxy-pyrrolidin-1-yl)-[10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-1-
0H-phenothiazin-3-yl]-methanone, 2r was obtained as TFA salt and as
a mixture of endo and exo isomers after purification via reverse
phase HPLC (eluent gradient: 20% to 45% CH.sub.3CN in water
containing 0.1% TFA). MS m/z=436.2 (M+1).
##STR00080##
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide, 3r
[0541] Using an adaptation of Procedure 27, substituting ethylamine
for pyrrolidine, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide, 3r was obtained as TFA salt and as a mixture of
endo and exo isomers after purification via reverse phase HPLC
(eluent gradient: 20% to 45% CH.sub.3CN in water containing 0.1%
TFA). MS m/z=394.2 (M+1).
Example T
##STR00081##
[0542]
Endo-3-(3-Diethylcarbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester, 1t
[0543] Using an adaptation of Procedure 6, and substituting
endo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b for
3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b, the title compound
endo-3-(3-diethylcarbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-
-carboxylic acid tert-butyl ester, 1t was obtained. The crude
material was used as such in the next reaction.
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t
[0544] Using an adaptation of Procedure 25, substituting
endo-3-(3-diethylcarbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-
-carboxylic acid tert-butyl ester, 1t for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, and using a 25% solution of TFA
in methylene chloride instead of neat TFA, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t was obtained as a TFA salt after purification
via reverse phase HPLC (eluent: CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 392.1.
Endo-10-[8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide, 3t
[0545] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, thiophene-2-carboxaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
endo-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-
-phenoxazine-3-carboxylic acid diethylamide, 3t was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
488.1.
##STR00082##
Endo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide, 4t
[0546] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
endo-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H--
phenoxazine-3-carboxylic acid diethylamide, 4t was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
483.1.
##STR00083##
Endo-10-(8-Thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide, 5t
[0547] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, thiazol-2-ylmethyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
endo-10-(8-thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H--
phenoxazine-3-carboxylic acid diethylamide, 5t was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
489.1.
##STR00084##
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carb-
oxylic acid diethylamide, 6t
[0548] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, phenyl acetaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxy-borohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloro-ethane, the
title compound
endo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide, 6t was obtained as a TFA salt
after purification via reverse phase HPLC (eluent: CH.sub.3CN in
water containing 0.1% TFA).
##STR00085##
Endo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide, 7t
[0549] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, 3-pyridyl carboxaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxy-borohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloro-ethane, the
title compound
endo-10-(8-pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H--
phenoxazine-3-carboxylic acid diethylamide, 7t was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
483.1.
##STR00086##
Endo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicycio[3.2.1]oct-3-yl]-10H-phenox-
azine-3-carboxylic acid diethylamide
[0550] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, 3-methyl-but-2-enyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
endo-10-[8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-1-
0H-phenoxazine-3-carboxylic acid diethylamide, 8t was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
460.1.
##STR00087##
Endo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phe-
noxazine-3-carboxylic acid diethylamide, 9t
[0551] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, 1H-imidazol-2-ylmethyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
endo-10-[8-(1H-imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl-
]-10H-phenoxazine-3-carboxylic acid diethylamide, 9t was obtained
as a TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
472.1.
##STR00088##
Endo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxy-
lic acid diethylamide, 10t
[0552] Using an adaptation of Procedure 9, and substituting
endo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2t for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, benzaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
endo-10-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxy-
lic acid diethylamide, 10t was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 482.1.
Example U
##STR00089##
[0553]
Exo-3-(3-Diethylcarbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oct-
ane-8-carboxylic acid tert-butyl ester, 1u
[0554] Using an adaptation of Procedure 6, and substituting
exo-3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 2b for
3-(2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1b, the title compound
exo-3-(3-diethylcarbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8--
carboxylic acid tert-butyl ester, 1u was obtained. The crude
material was used as such in the next reaction.
Exo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u
[0555] Using an adaptation of Procedure 25, substituting
exo-3-(3-diethylcarbamoyl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8--
carboxylic acid tert-butyl ester, 1u for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, and using a 25% solution of TFA
in methylene chloride instead of neat TFA, the title compound
exo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u was obtained as a TFA salt after purification
via reverse phase HPLC (eluent: CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 392.1.
Exo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carbox-
ylic acid diethylamide, 3u
[0556] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, phenyl acetaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxy-borohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloro-ethane, the
title compound
exo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide, 3u was obtained as a TFA salt
after purification via reverse phase HPLC (eluent: CH.sub.3CN in
water containing 0.1% TFA). MS m/z (MH.sup.+)
##STR00090##
Exo-10-(8-Pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide, 4u
[0557] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, 3-pyridyl carboxaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxy-borohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloro-ethane, the
title compound
exo-10-(8-pyridin-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-p-
henoxazine-3-carboxylic acid diethylamide, 4u was obtained as a TFA
salt after purification via reverse phase HPLC (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 483.1.
##STR00091##
Exo-10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazi-
ne-3-carboxylic acid diethylamide, 5u
[0558] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, thiophene-2-carboxaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
exo-10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H--
phenoxazine-3-carboxylic acid diethylamide, 5u was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
488.1.
##STR00092##
Exo-10-[8-(3-Methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phenoxa-
zine-3-carboxylic acid diethylamide, 6u
[0559] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, 3-methyl-but-2-enyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
exo-10-[8-(3-methyl-but-2-enyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10-
H-phenoxazine-3-carboxylic acid diethylamide, 6u was obtained as a
TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
460.1.
##STR00093##
Exo-10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide, 7u
[0560] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
exo-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-p-
henoxazine-3-carboxylic acid diethylamide, 7u was obtained as a TFA
salt after purification via reverse phase HPLC (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 483.1.
##STR00094##
Exo-10-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxyl-
ic acid diethylamide, 8u
[0561] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, benzaldehyde for 2-pyridyl carboxaldehyde,
tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
exo-10-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxyl-
ic acid diethylamide, 8u was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 482.1.
##STR00095##
Exo-10-(8-Thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-
e-3-carboxylic acid diethylamide, 9u
[0562] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, thiazol-2-ylmethyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
exo-10-(8-thiazol-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-p-
henoxazine-3-carboxylic acid diethylamide, 9u was obtained as a TFA
salt after purification via reverse phase HPLC (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 489.1.
##STR00096##
Exo-10-(8-Furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine--
3-carboxylic acid diethylamide, 10u
[0563] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, thiazol-2-ylmethyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
exo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]-oct-3-yl)-10H-ph-
enoxazine-3-carboxylic acid diethylamide, 10u was obtained as a TFA
salt after purification via reverse phase HPLC (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 472.1.
##STR00097##
Exo-10-[8-(1H-Imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phen-
oxazine-3-carboxylic acid diethylamide, 11 u
[0564] Using an adaptation of Procedure 9, and substituting
exo-10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 2u for
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 5b, 1H-imidazol-2-ylmethyl carboxaldehyde for 2-pyridyl
carboxaldehyde, tetrabutylammonium triacetoxyborohydride for sodium
triacetoxyborohydride, and tetrahydrofuran for dichloroethane, the
title compound
xxo-10-[8-(1H-imidazol-2-ylmethyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-
-10H-phenoxazine-3-carboxylic acid diethylamide, 11u was obtained
as a TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (M H.sup.+)
472.1.
Example V
##STR00098##
[0565]
Endo-3-(3-Chloro-6-methoxy-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester, 1v
[0566] Using an adaptation of Procedure 2, and substituting
6-fluoro-2-methoxy-nitrobenzene, 1e for
4-fluoro-3-nitrobenzonitrile and
endo-3-(4-chloro-2-hydroxy-phenylamino)-8-aza-bicyclo[3.2.1]octane-8-carb-
oxylic acid tert-butyl ester, 1j for the TFA salt of
3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic
acid methyl ester, 1a, the title compound
endo-3-(3-chloro-6-methoxy-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-
-carboxylic acid tert-butyl ester, 1v was obtained. MS m/z
(MH.sup.+) 457.2.
Endo-3-(6-Methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oct-
ane-8-carboxylic acid tert-butyl ester, 2v
[0567] Using an adaptation of the method described in Procedure 24,
substituting
endo-3-(3-chloro-6-methoxy-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-
-carboxylic acid tert-butyl ester, 1v for
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]-octane-8-carboxyli-
c acid tert-butyl ester, 3j, the title compound
endo-3-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester, 2v was obtained. MS m/z
(MH.sup.+) 500.3.
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenoxazin-4-ol,
3v
[0568] Using an adaptation of the method described in Procedure 16,
substituting
endo-3-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester, 2v for the TFA salt of
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenoxazin-4-ol-
, 3v was obtained as a TFA salt after purification via reverse
phase chromatography (eluent: CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 386.1.
Endo-7-Pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-
-10H-phenoxazin-4-ol, 4v
[0569] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenoxazin-4-ol-
, 3v for 4-amino-3-hydroxybenzoic acid methyl ester, and 2-pyridyl
carboxaldehyde for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the
title compound
endo-7-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1-
]oct-3-yl)-10H-phenoxazin-4-ol, 4v was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 477.2.
##STR00099##
Endo-10-(8-Aza-bicyclo[3.2.1
]oct-3-yl)-3-chloro-6-methoxy-10H-phenoxazine, 5v
[0570] Using an adaptation of the method described in Procedure 25,
substituting the TFA salt of
endo-7-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazin-4-ol, 4v for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-chloro-6-methoxy-10H-phenoxazine-
, 5v was obtained as a TFA salt after purification via reverse
phase chromatography (eluent: CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 357.1.
##STR00100##
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-10H-pheno-
xazine, 6v
[0571] Using an adaptation of the method described in Procedure 25,
substituting
endo-3-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester, 2v for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-10H-pheno-
xazine, 6v was obtained as a TFA salt after purification via
reverse phase chromatography (eluent: CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 400.2.
##STR00101##
Endo-6-Methoxy-3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine, 7v
[0572] Using an adaptation of the method described in Procedure 1,
substituting
endo-3-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]oc-
tane-8-carboxylic acid tert-butyl ester, 2v for
4-amino-3-hydroxybenzoic acid methyl ester, and 2-pyridyl
carboxaldehyde for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the
title compound
endo-6-methoxy-3-pyridin-3-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine, 7v was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 491.2.
##STR00102##
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazin-4-ol-
, 8v
[0573] Using an adaptation of the methods described in Procedures
24 and 16, substituting
endo-3-(3-chloro-6-methoxy-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-
-carboxylic acid tert-butyl ester, 1v for
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]-octane-8-carboxyli-
c acid tert-butyl ester, 3j, and 4-pyridylboronic acid for
3-pyridylboronic acid in Procedure 24, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazin-4-ol-
, 8v was obtained as a TFA salt after purification via reverse
phase chromatography (eluent: CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 386.2.
##STR00103##
Endo-7-Pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl-
)-10H-phenoxazin-4-ol, 9v
[0574] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazin-4-ol-
, 8v for 4-amino-3-hydroxybenzoic acid methyl ester, and 2-pyridyl
carboxaldehyde for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the
title compound
endo-7-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1-
]oct-3-yl)-10H-phenoxazin-4-ol, 9v was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 477.3.
##STR00104##
Endo-10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phe-
noxazin-4-ol, 10v
[0575] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-yl-10H-phenoxazin-4-ol-
, 8v for 4-amino-3-hydroxybenzoic acid methyl ester, and phenyl
acetaldehyde for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the
title compound
endo-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-4-y-
l-10H-phenoxazin-4-ol, 10v was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 490.3.
##STR00105##
Endo-10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-4-yl-10H-pheno-
xazine, 11v
[0576] Using an adaptation of the methods described in Procedures
24 and 25, substituting
endo-3-(3-chloro-6-methoxy-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-
-carboxylic acid tert-butyl ester, 1v for
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]-octane-8-carboxyli-
c acid tert-butyl ester, 3j, and 4-pyridylboronic acid for
3-pyridylboronic acid in Procedure 24, the title compound
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-4-yl-10H-pheno-
xazine, 11v was obtained as a TFA salt after purification via
reverse phase chromatography (eluent: CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 400.2.
##STR00106##
Endo-6-Methoxy-3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-10H-phenoxazine, 12v
[0577] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-4-yl-10H-pheno-
xazine, 11v for 4-amino-3-hydroxybenzoic acid methyl ester, and
2-pyridyl carboxaldehyde for
8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the title compound
endo-6-methoxy-3-pyridin-4-yl-10-(8-pyridin-2-ylmethyl-8-aza-bic-
yclo[3.2.1]oct-3-yl)-10H-phenoxazine, 12v was obtained as a TFA
salt after purification via reverse phase chromatography (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
491.2.
##STR00107##
Endo-6-Methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-pyridin-4--
yl-10H-phenoxazine, 13v
[0578] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-4-yl-10H-pheno-
xazine, 11v for 4-amino-3-hydroxybenzoic acid methyl ester, and
phenyl acetaldehyde for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one,
the title compound
endo-6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-p-
yridin-4-yl-10H-phenoxazine, 13v was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 504.3.
Example X
##STR00108##
[0579]
Endo-3-[3-(2-Acetylaminophenyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2-
.1]octane-8-carboxylic acid tert-butyl ester, 1x
[0580] Using an adaptation of the method described in Procedure 24,
substituting
N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide
for 3-pyridyl boronic acid, the title compound
endo-3-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]oct-
ane-8-carboxylic acid tert-butyl ester, 1x was obtained as a TFA
salt after purification via reverse phase chromatography (eluent:
CH.sub.3CN in water containing 0.1% TFA).
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}--
acetamide, 2x
[0581] Using an adaptation of Procedure 25, substituting the TFA
salt of
endo-3-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-8-aza-bicyclo[3.2.1]oct-
ane-8-carboxylic acid tert-butyl ester, 1x for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, the title compound
endo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide, 2x was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in water containing 0.1%
TFA). MS m/z (MH.sup.+) 426.2.
Endo-N-{2-[10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3--
yl]-phenylyacetamide, 3x
[0582] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide, 2x for 4-amino-3-hydroxybenzoic acid methyl ester, and
phenyl acetaldehyde for 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one,
the title compound
endo-N-{2-[10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phe-
noxazin-3-yl]-phenyl}-acetamide, 3x was obtained as a TFA salt
after purification via reverse phase chromatography (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
530.3.
##STR00109##
Endo-N-{2-[10-(8-Thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enoxazin-3-yl]-phenyl}-acetamide, 4x
[0583] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide, 2x for 4-amino-3-hydroxybenzoic acid methyl ester, and
2-thiophene carboxaldehyde for
8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the title compound
endo-N-{2-[10-(8-thiophen-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enoxazin-3-yl]-phenyl}-acetamide, 4x was obtained as a TFA salt
after purification via reverse phase chromatography (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
522.2.
##STR00110##
Endo-N-{2-[10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl]-10H-phe-
noxazin-3-yl]-phenylyacetamide, 5x
[0584] Using an adaptation of the method described in Procedure 1,
substituting the TFA salt of
endo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide, 2x for 4-amino-3-hydroxybenzoic acid methyl ester, and
2-pyridyl carboxaldehyde for
8-methyl-8-aza-bicyclo[3.2.1]octan-3-one, the title compound
endo-N-{2-[10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phe-
noxazin-3-yl]-phenyl}-acetamide, 5x was obtained as a TFA salt
after purification via reverse phase chromatography (eluent:
CH.sub.3CN in water containing 0.1% TFA). MS m/z (MH.sup.+)
517.2.
Example Y
##STR00111##
[0585]
Exo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-ph-
enyl}-acetamide, 1y
[0586] Using an adaptation of the methods described in Procedures
24 and 25, and substituting
exo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 1l for
endo-3-(3-chlorophenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3j, and
N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide
for 3-pyridyl boronic acid in Procedure 24, the title compound
exo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazin-3-yl]-phenyl}--
acetamide, 1y was obtained as a TFA salt after purification via
reverse phase chromatography (eluent: CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 426.2.
Example Z
##STR00112##
[0587]
Endo-3-[3-(2-Acetylaminophenyl)-6-methoxy-phenoxazin-10-yl]-8-aza-b-
icyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1z
[0588] Using an adaptation of the method described in Procedure 24,
substituting
N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide
for 3-pyridyl boronic acid, the title compound
endo-3-[3-(2-acetylaminophenyl)-6-methoxy-phenoxazin-10-yl]-8-aza-bicyclo-
[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1z was obtained
as a TFA salt after purification via reverse phase chromatography
(eluent: CH.sub.3CN in water containing 0.1% TFA).
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenoxazin-3-yl-
]-phenyl}-acetamide, 2z
[0589] Using an adaptation of the method described in Procedure 16,
substituting the TFA salt of
endo-3-[3-(2-acetylaminophenyl)-6-methoxy-phenoxazin-10-yl]-8-aza-bicyclo-
[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1z for the TFA
salt of
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e, the title compound
endo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenoxazin-3-y-
l]-phenyl}-acetamide, 2z was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 442.2.
##STR00113##
Endo-N-{2-[10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazin-3-y-
l]-phenylyacetamide, 3z
[0590] Using an adaptation of the method described in Procedure 25,
substituting the TFA salt of
endo-3-[3-(2-acetylaminophenyl)-6-methoxy-phenoxazin-10-yl]-8-aza-bicyclo-
[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1z for
endo-3-(3-pyridin-3-yl-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-car-
boxylic acid tert-butyl ester, 4j, the title compound
endo-N-{2-[10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenoxazin-3-y-
l]-phenyl}-acetamide, 3z was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA). MS m/z (MH.sup.+) 456.2.
Example AA
##STR00114##
[0591] Procedure 28
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile,
1aa
[0592] To a solution of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-10H-phenothiazine, 4i (50
mg, 0.13 mmol) in DMF (750 .mu.L) was added zinc cyanide (15 mg,
0.13 mmol) and tetrakistriphenylphosphine palladium (4 mg), the
solution was purged with nitrogen, and the mixture was heated in
the microwave for 5 min at 160.degree. C. The mixture was allowed
to cool to rt, and purified via reverse phase HPLC (eluent:
CH.sub.3CN in water containing 0.1% TFA) to yield title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile,
1aa as a TFA salt and as a mixture of endo and exo isomers. MS m/z
(MH.sup.+) 334.1.
10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonit-
rile, 2aa
[0593] Using an adaptation of the method described in Procedure 22,
substituting the TFA salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile,
1aa for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i, the title
compound
10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboni-
trile, 2aa was obtained as a TFA salt after purification via
reverse phase chromatography (eluent: CH.sub.3CN in water
containing 0.1% TFA) and as a mixture of endo and exo isomers.
Procedure 29
10-(8-Phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phe-
nothiazine, 3aa
[0594] To a solution of
10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboni-
trile, 2aa (10 mg, 29 .mu.mol) in dimethoxyethane was added
trimethylsilyl azide (15 .mu.L, 115 .mu.mol) and dibutyltin oxide
(1.5 mg), and the mixture was heated in a microwave for 15 min at
150.degree. C. The mixture was allowed to cool to rt, and purified
via reverse phase HPLC (eluent: CH.sub.3CN in water containing 0.1%
TFA) to yield title compound
10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-ph-
enothiazine, 3aa as a TFA salt and as a mixture of endo and exo
isomers. MS m/z (MH.sup.+) 481.2.
##STR00115##
10-(8-Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-y-
l)-10H-phenothiazine, 4aa
[0595] Using an adaptation of the methods described in Procedures
22 and 29, substituting the TFA salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile,
1aa for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i and
2-pyridyl carboxaldehyde for 3-furyl carboxaldehyde in Procedure
22, the title compound
10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tet-
razol-5-yl)-10H-phenothiazine, 4aa was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA) and as a mixture of endo and exo
isomers. MS m/z (MH.sup.+) 468.2.
##STR00116##
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine,
5aa
[0596] Using an adaptation of the method described in Procedure 29,
substituting the TFA salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile,
1aa for
10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-car-
bonitrile, 2aa, the title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine,
5aa was obtained as a TFA salt after purification via reverse phase
chromatography (eluent: CH.sub.3CN in water containing 0.1% TFA)
and as a mixture of endo and exo isomers.
[0597] MS m/z (MH.sup.+) 377.2.
##STR00117##
N,N-Diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazi-
ne-3-carboxamidine, 6aa
[0598] Using an adaptation of the method described in Procedure 10,
substituting the TFA salt of
10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboni-
trile, 2aa for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b, the title compound
N,N-diethyl-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazi-
ne-3-carboxamidine, 6aa was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA) and as a mixture of endo and exo
isomers. MS m/z (MH.sup.+) 511.3.
##STR00118##
N,N-Diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enothiazine-3-carboxamidine, 7aa
[0599] Using an adaptation of the methods described in Procedures
22 and 10, substituting the TFA salt of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitrile,
1aa for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 3b, and 2-pyridyl carboxaldehyde for
3-furyl carboxaldehyde, the title compound
N,N-diethyl-10-(8-pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-ph-
enothiazine-3-carboxamidine, 7aa was obtained as a TFA salt after
purification via reverse phase chromatography (eluent: CH.sub.3CN
in water containing 0.1% TFA) and as a mixture of endo and exo
isomers.
[0600] MS m/z (MH.sup.+) 498.3.
Example BB
##STR00119##
[0601]
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carb-
onitrile, 1bb
[0602] Using an adaptation of the method described in Procedure 28,
substituting
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carbox-
ylic acid tert-butyl ester, 3b, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitri-
le, 1bb was obtained as a TFA salt after purification via reverse
phase chromatography (eluent: CH.sub.3CN in water containing 0.1%
TFA) and as a mixture of endo and exo isomers. MS m/z (MH.sup.+)
348.1.
10-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-phenot-
hiazine, 2bb
[0603] Using an adaptation of the method described in Procedure 29,
substituting the TFA salt of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitri-
le, 1bb for
10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carboni-
trile, 2aa, the title compound
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-3-(1H-tetrazol-5-yl)-10H-pheno-
thiazine, 2bb was obtained as a TFA salt after purification via
reverse phase chromatography (eluent: CH.sub.3CN in water
containing 0.1% TFA) and as a mixture of endo and exo isomers.
[0604] MS m/z (MH.sup.+) 391.1.
##STR00120##
N,N-Diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine--
3-carboxamidine, 3bb
[0605] Using an adaptation of the method described in Procedure 10,
substituting the TFA salt of
10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine-3-carbonitri-
le, 1bb for
endo-3-(3-cyano-phenoxazin-10-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid tert-butyl ester, 3b, the title compound
N,N-diethyl-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine--
3-carboxamidine, 3bb was obtained as a TFA salt after purification
via reverse phase chromatography (eluent: CH.sub.3CN in water
containing 0.1% TFA) and as a mixture of endo and exo isomers. MS
m/z (MH.sup.+) 421.2.
Example CC
##STR00121## ##STR00122##
[0606] Spiro Compound, 1cc
[0607] Using an adaptation of the method described in Procedure 18,
substituting for 2-amino-5-bromothiophenol for 2-aminothiophenol,
the title compound 1cc was obtained.
[2-(3-Methoxy-2-nitro-phenylsulfanyl)-phenyl]-(8-methyl-8-aza-bicyclo[3.2.-
1]oct-3-yl)-amine, 2cc
[0608] Using an adaptation of the method described in Procedure 19,
substituting spiro compound, 1cc for spiro compound 1i, the title
compound
[2-(3-methoxy-2-nitro-phenylsulfanyl)-phenyl]-(8-methyl-8-aza-bi-
cyclo[3.2.1]oct-3-yl)-amine, 2cc was obtained a mixture of endo and
exo isomers.
3-Bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothia-
zine, 3cc
[0609] Using an adaptation of the method described in Procedure 20,
substituting
[2-(3-methoxy-2-nitro-phenylsulfanyl)-phenyl]-(8-methyl-8-aza-bicyclo[3.2-
.1]oct-3-yl)-amine, 2cc for
[2-(4-bromo-2-nitrophenylsulfanyl)-phenyl]-(8-methyl-8-aza-bicyclo[3.2.1]-
oct-3-yl)-amine, 2i, the title compound
3-bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine, 3cc was obtained a mixture of endo and exo isomers.
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine,
4cc
[0610] Using an adaptation of the method described in Procedure 21,
substituting
3-bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine 3cc for
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i, the title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine,
4cc was obtained a mixture of endo and exo isomers.
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-bromo-10H-phenothiazin-4-ol,
5cc
[0611] Using an adaptation of the method described in Procedure 16,
substituting
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine,
4cc for
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-pheno-
xazine-3-carboxylic acid diethylamide, 6e, a mixture of title
compound
10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-7-bromo-10H-phenothiazin-4-ol,
5cc and starting material
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine,
4cc was obtained a mixture of endo and exo isomers.
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-10H-phenothiazi-
ne, 6cc and
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenothiazin-4-ol,
7cc
[0612] Using an adaptation of the method described in Procedure 23,
substituting a mixture of
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-3-bromo-6-methoxy-10H-phenothiazine,
4cc and
10-(8-aza-bicyclo-[3.2.1]oct-3-yl)-7-bromo-10H-phenothiazin-4-ol,
5cc for
3-bromo-10-(8-furan-3-ylmethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H--
phenothiazine, 5i, a mixture of title compounds
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-3-pyridin-3-yl-10H-phenothiaz-
ine, 6cc and
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-7-pyridin-3-yl-10H-phenothiazin-4-ol,
7cc was obtained. The compounds were separated via reverse phase
HPLC (eluent: CH3CN in water containing 0.1% TFA) to yield 6cc [MS
m/z (MH.sup.+) 416.2] and 7cc [MS m/z (MH.sup.+) 402.2], bothy as
TFA salts and mixtures of endo and exo isomers.)
Example DD
##STR00123##
[0613]
6-Methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiaz-
ine-3-carboxylic acid diethylamide, 1dd
[0614] Using an adaptation of the method described in Procedure 26,
substituting a mixture of endo and exo isomers of
3-bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine, 3cc for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 4i,
title compound
6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoth-
iazine-3-carboxylic acid diethylamide, 1dd was obtained as a
mixture of endo and exo isomers.
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenothiazine-3-carboxylic
acid diethylamide, 2dd
[0615] Using an adaptation of the method described in Procedure 21,
substituting
3-bromo-6-methoxy-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothi-
azine, 3cc for
3-bromo-10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenothiazine,
3i, title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenothiazine-3-carboxyli-
c acid diethylamide, 2dd was obtained as a TFA salt and as a
mixture of endo and exo isomers.
10-(8-Aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenothiazine-3-carboxylic
acid diethylamide, 3dd
[0616] Using an adaptation of the method described in Procedure 16,
substituting
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-methoxy-10H-phenothiazine-3-carboxyli-
c acid diethylamide, 2dd for
6-methoxy-10-(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-
-carboxylic acid diethylamide, 6e, a mixture of title compound
10-(8-aza-bicyclo[3.2.1]oct-3-yl)-6-hydroxy-10H-phenothiazine-3-carboxyli-
c acid diethylamide, 3dd was obtained. MS m/z (MH.sup.+) 424.2.
Biological Examples
Rat Brain Delta Opioid Receptor Binding Assay
[0617] Procedure: Male, Wistar rats (150-250 g, VAF, Charles River,
Kingston, N.Y.) were killed by CO.sub.2, and their brains were
removed and placed immediately in ice cold Tris HCl buffer (50 mM,
pH 7.4). The forebrains were separated from the remainder of the
brain by a coronal transection, beginning dorsally at the colliculi
and passing ventrally through the midbrain-pontine junction. After
dissection, the forebrains were homogenized in Tris buffer in a
Teflon.RTM.-glass homogenizer. The homogenate was diluted to a
concentration of 1 g of forebrain tissue per 80 mL Tris and
centrifuged at 39,000.times.g for 10 min. The pellet was
resuspended in the same volume of Tris buffer containing 5 mM
MgCl.sub.2 with several brief pulses from a Polytron homogenizer.
This particulate preparation was used for the delta opioid binding
assays. Following incubation with the delta selective peptide
ligand .about.4 nM [.sup.3H]DPDPE or 0.15 nM [.sup.3H]naltrindole
at 25.degree. C. for 2.5 h in a 96-well plate with total volume of
1 mL, the plate contents were filtered through Wallac filtermat B
sheets on a Tomtec 96-well harvester. The filters were rinsed three
times with 2 mL of 10 mM HEPES (pH 7.4), and dried in a 650 W
microwave oven for 1.75 min twice. To each sample area 2.times.50
.mu.L of Betaplate Scint scintillation fluid (LKB) was added and
the radioactivity quantified on a LKB (Wallac) 1205 BetaPlate
liquid scintillation counter.
[0618] Analysis: The data from the scintillation counter were used
to calculate either the % inhibition compared to control binding
(when only a single concentration of test compound was evaluated)
or a K.sub.i value (when a range of concentrations was tested).
Percent inhibition was calculated as: [(total dpm-test compound
dpm)/(total dpm-nonspecific dpm)]*100. Kd and Ki values were
calculated using GraphPad PRISM data analysis program.
Rat Brain Mu Opioid Receptor Binding Assay
[0619] Procedure: Male, Wistar rats (150-250 g, VAF, Charles River,
Kingston, N.Y.) were killed by CO.sub.2, and their brains were
removed and placed immediately in ice cold Tris HCl buffer (50 mM,
pH 7.4). The forebrains were separated from the remainder of the
brain by a coronal transection, beginning dorsally at the colliculi
and passing ventrally through the midbrain-pontine junction. After
dissection, the forebrains were homogenized in Tris buffer in a
Teflon.RTM.-glass homogenizer. The homogenate was diluted to a
concentration of 1 g of forebrain tissue per 80 mL Tris and
centrifuged at 39,000.times.g for 10 min. The pellet was
resuspended in the same volume of Tris buffer containing 5 mM
MgCl.sub.2 with several brief pulses from a Polytron homogenizer.
This particulate preparation was used for the delta opioid binding
assays. Following incubation with the mu selective peptide ligand,
.about.0.8 nM [.sup.3H]DAMGO, at 25.degree. C. for 2.5 h in a
96-well plate with total assay volume of 1 mL, the plate contents
were filtered through Wallac filtermat B sheets on a Tomtec 96-well
harvester. The filters were rinsed three times with 2 mL of 10 mM
HEPES (pH 7.4), and dried in a 650 W microwave oven for 1.75 min
twice. To each sample area 2.times.40 .mu.L of Betaplate Scint
scintillation fluid (LKB) was added and the radioactivity quantifed
on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.
[0620] Analysis: The data from the scintillation counter were used
to calculate either the % inhibition compared to control binding
(when only a single concentration of test compound was evaluated)
or a K.sub.1 value (when a range of concentrations tested). Percent
inhibition was calculated as: [(total dpm-test compound dpm)/(total
dpm-nonspecific dpm)]*100. Kd and Ki values were calculated using
GraphPad PRISM data analysis program.
[.sup.35S]GTP.gamma.S Binding Assay in NG108-15 Cell Membranes
(delta opioid)
[0621] Methods: NG108-15 cell membranes can be purchased from
Applied Cell Sciences (Rockville, Md.). 8 mg/mL of membrane protein
suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose.
Membranes can be maintained at 4-8.degree. C. A 1 mL volume of
membranes can be added into 10 mL cold binding assay buffer. The
assay buffer contained 50 mM Tris, pH 7.6, 5 mM MgCl.sub.2, 100 mM
NaCl, 1 mM DTT and 1 mM EGTA. The membrane suspension can be
homogenized twice with a Polytron, and centrifuged at 3000 rpm for
10 min. The supernatant can be then centrifuged at 18,000 rpm for
20 min. Ten mL assay buffer can be added into the pellet containing
tube. The pellet and buffer can be mixed with a Polytron.
[0622] Incubation procedure: The pellet membranes (75 .mu.g/mL) can
be preincubated with SPA (10 mg/mL) at 25.degree. C. for 45 min in
the assay buffer. The SPA (5 mg/mL) coupled with membranes (37.5
.mu.g/mL) can then be incubated with 0.1 nM [.sup.353] GTP.gamma.S
in the same Tris buffer containing 100 .mu.M GDP in total volume of
200 .mu.L. Increasing concentrations of receptor agonists can be
used to stimulate [.sup.355]-GTP S binding. The basal binding can
be tested in the absence of agonists and non-specific binding can
be tested in the presence of 10 .mu.M unlabeled GTP.gamma.S. The
data can be analyzed on a Packard Top Count. DATA [0623] % of
Basal=(stimulated--non specific)*100/(basal--non specific). [0624]
EC.sub.50 value values can be calculated using GraphPad Prism.
[.sup.35S]GTP.gamma.S Binding Assays in CHO-hMOR Cell Membranes
[0625] Methods: CHO-hMOR cell membranes can be purchased from
Receptor Biology, Inc. (Baltimore, Md.). About 10 mg/mL of membrane
protein can be suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10%
sucrose, and the suspension kept on ice. A 1 mL volume of membranes
can be added to 15 mL cold binding assay buffer containing 50 mM
HEPES, pH 7.6, 5 mM MgCl.sub.2, 100 mM NaCl, 1 mM DTT and 1 mM
EDTA. The membrane suspension can be homogenized with a Polytron
and centrifuged at 3,000 rpm for 10 min. The supernatant can then
be centrifuged at 18,000 rpm for 20 min. The pellet can be
resuspended in 10 mL assay buffer with a Polytron. The membranes
can be preincubated with wheat germ agglutinin coated SPA beads
(Amersham) at 25.degree. C. for 45 min in the assay buffer. The SPA
bead (5 mg/mL) coupled membranes (10 .mu.g/mL) can be then
incubated with 0.5 nM [.sup.35S]GTP.gamma.S in the assay buffer.
The basal binding can be that taking place in the absence of added
test compound; this unmodulated binding can be considered as 100%,
with agonist stimulated binding rising to levels significantly
above this value. A range of concentrations of receptor agonist can
be used to stimulate [.sup.35S]GTP.gamma.S binding. Both basal and
non-specific binding can be tested in the absence of agonist;
non-specific binding determination included 10 .mu.M unlabeled
GTP.gamma.S.
[0626] Compounds can be tested for function as antagonists by
evaluating their potential to inhibit agonist-stimulated
GTP.gamma.S binding. Radioactivity can be quantified on a Packard
TopCount. The following parameters can be calculated:
% stimulation = ( test compound cpm - non - specific cpm ) ( basal
cpm - non - specific cpm ) .times. 100. ##EQU00003## % inhibition =
( % stimulation by 1 M DAMGO - % stimulation by test compound ) ( %
stimulation by 1 M DAMGO - 100 ) .times. 100 ##EQU00003.2## [0627]
EC.sub.50 values can be calculated using Graph Pad Prism.
TABLE-US-00001 [0627] Biological Data Compound Number delta (Ki,
nM) mu (Ki, nM) 4t 0.1 4aa 0.1 6b 0.1 168.45 6d 0.1 336 9t 0.10 8t
0.18 4v 0.3 2z 0.62 10t 1.14 7e 2.2 7t 2.43 7u 3.27 8v 5.2 3v 8.3
8j 18.8 8u 20.70 3t 25.1 3z 27.63 12v 36.3 6u 44.49 3c 48.1 525 7v
56.6 5t 56.7 5x 81.82 2t 86.6 6e 99.5 7j 103.6 7i 122.84 554.3 9v
136.3 4x 161.3 2u 196.5 6t 231.0 5k 246.7 6v 263.2 6i 282.35 1055.7
4e 320.9 5aa 321.1 11i 366.9 170.985 4a 373 6761 3r 396.8 682.2 11v
399.5 5b 406 6849 5j 409.4 2x 414.6 4l 424.6 8i 443.5 889.4 4k
444.8 5u 477.80 3m 480.1 12i 491.45 1450 2c 492 9448 5l 539.2 4u
542.55 13i 551.6 3740 6a 575 819 2h 598 2889 17i 629 1533.5 15i
629.55 168.9 2m 634.2 9i 649.35 538.4 1r 651.95 2758 2k 695.5 2a
697 5152 3l 729.1 2r 863.65 4340 4p 864.5 4m 868.9 4i 881 6613 1aa
930.9 18i 940.75 8073 10i 949.05 317.3 6l 1269.1 5m 1278.5 3u
1356.30 16i 1453 2654 3x 1585.0 1y 1601.8 14i 1603.5 598.75 3f 1752
1435 8b 1896 >10000 1g 2041 4285 5a 2116 6091 5v 2260.0 3i 2532
3185 7d 2633 123 2f 2644.5 2752 4c 3106 89.0 6j 3261.5 3k 3388.0 3p
5123.0 19i 5191 254 7b 5475 288 7l 6211.5 9j 11865.0 10j 13321.5 6k
14223.5 10v >10000 13v >10000
* * * * *