U.S. patent application number 12/196865 was filed with the patent office on 2008-12-25 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 | 20080318937 12/196865 |
Document ID | / |
Family ID | 36508108 |
Filed Date | 2008-12-25 |
United States Patent
Application |
20080318937 |
Kind Code |
A1 |
Coats; Steven J. ; et
al. |
December 25, 2008 |
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.;
(Quakertown, 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: |
36508108 |
Appl. No.: |
12/196865 |
Filed: |
August 22, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11326084 |
Jan 5, 2006 |
7432257 |
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12196865 |
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60641699 |
Jan 6, 2005 |
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Current U.S.
Class: |
514/225.5 ;
514/229.8; 544/102; 544/104; 544/43; 544/46 |
Current CPC
Class: |
A61P 1/12 20180101; A61P
7/12 20180101; A61P 29/00 20180101; A61P 11/00 20180101; C07D
417/14 20130101; A61P 25/00 20180101; A61P 17/02 20180101; A61P
25/16 20180101; A61P 9/10 20180101; A61P 15/00 20180101; A61P 1/04
20180101; C07D 413/04 20130101; A61P 13/08 20180101; A61P 11/02
20180101; A61P 37/06 20180101; A61P 17/04 20180101; A61P 25/04
20180101; C07D 413/14 20130101; C07D 417/04 20130101; A61P 25/18
20180101; A61P 17/00 20180101; A61P 13/10 20180101; A61P 19/02
20180101; A61P 17/16 20180101; A61P 25/06 20180101; A61P 25/32
20180101 |
Class at
Publication: |
514/225.5 ;
544/43; 544/46; 544/102; 544/104; 514/229.8 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; C07D 417/14 20060101 C07D417/14; C07D 413/14 20060101
C07D413/14; A61K 31/538 20060101 A61K031/538; A61P 25/00 20060101
A61P025/00 |
Claims
1. A compound of Formula (I): ##STR00099## 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 the C.sub.6-10aryl 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; 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.1-6alkanylamino,
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; 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;
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--; 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.1-6alkanylaminocarbonyl, 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;
R.sub.6 is one to four 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; Y
is O or S; 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.
2. The compound 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,
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.
3. The compound 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, 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.
4. The compound 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, hydroxy(C.sub.1-4)alkanyl,
C.sub.1-4alkanylcarbonylamino, hydroxy, cyano, oxo, thioxo, and
aminocarbonyl.
5. The compound 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, oxadiazolyl, and pyridinyl, wherein
the phenyl and the heterocycles of G are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-4alkanylcarbonylamino and oxo.
6. The compound according to claim 1 wherein G is
N,N-diethylaminocarbonyl, 2-methylcarbonylaminophenyl,
N--N-diethylamidino, pyridin-3-yl,
3-hydroxypyrrolidin-1-ylcarbonyl, N-ethylaminocarbonyl,
1H-tetrazol-4-yl, pyridine-4-yl, 4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
N,N-dimethylaminocarbonyl, or pyrrolidin-1-ylcarbonyl.
7. The compound according to claim 1 wherein R.sub.1 is a
substituent selected from the group consisting of hydrogen and
C.sub.1-4alkanyl.
8. The compound according to claim 1 wherein R.sub.1 is selected
from the group consisting of hydrogen, methyl, ethyl, and
propyl.
9. The compound according to claim 1 wherein R.sub.1 is selected
from the group consisting of hydrogen, methyl, and ethyl.
10. The compound according to claim 1 wherein R.sub.1 is selected
from the group consisting of hydrogen and ethyl.
11. The compound 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.
12. The compound 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.
13. The compound 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.
14. The compound according to claim 1 wherein R.sub.2 is selected
from the group consisting of hydrogen and C.sub.1-4alkanyl, 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.
15. The compound 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--.
16. The compound 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.
17. The compound according to claim 1 wherein R.sub.3 is hydrogen,
C.sub.1-8alkanyl, C.sub.2-8alkenyl, phenyl(C.sub.1-8)alkanyl, or
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is imidazolyl,
furanyl, pyridinyl, or thienyl.
18. The compound 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.
19. The compound according to claim 1 wherein R.sub.3 is hydrogen,
methyl, 3-methyl-2-butenyl, benzyl, phenethyl, or heteroarylmethyl
wherein the heteroaryl is furanyl, imidazolyl, pyridinyl, or
thienyl.
20. The compound 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.
21. The compound 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, aminocarbonyl, and
hydroxy.
22. The compound 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, aminocarbonyl, and hydroxy.
23. The compound according to claim 1 wherein R.sub.4 is one
substituent selected from the group consisting of hydrogen,
methoxy, hydroxyl, hydroxycarbonyl, and aminocarbonyl.
24. The compound according to claim 1 wherein R.sub.4 is one
substituent and is hydrogen, methoxy, or hydroxy.
25. The compound according to claim 1 wherein R.sub.5 is one to two
substituents independently selected from the group consisting of
hydrogen and halogen.
26. The compound according to claim 1 wherein R.sub.5 is
hydrogen.
27. The compound according to claim 1 wherein R.sub.6 is one to
four substituents independently selected from the group consisting
of hydrogen, C.sub.1-6alkanyl, C.sub.2-6alkenyl,
C.sub.1-6alkanyloxy, halogen, hydroxy, fluoro(C.sub.1-6)alkanyl and
fluoro(C.sub.1-6)alkanyloxy.
28. The compound according to claim 1 wherein R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4alkanyl.
29. The compound according to claim 1 wherein R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and methyl.
30. The compound according to claim 1 wherein R.sub.6 is
hydrogen.
31. The compound according to claim 1 wherein Y is O or S.
32. The compound according to claim 1 wherein Y is O.
33. The compound according to claim 1 wherein Z is O, NH,
N(C.sub.1-6alkanyl), N(OH), N(OC.sub.1-6alkanyl), or N(phenyl).
34. The compound according to claim 1 wherein Z is O, NH, or
N(OH).
35. The compound according to claim 1 wherein Z is O or NH.
36. The compound according to claim 1 wherein Z is O.
37. The compound according to claim 1 wherein R.sub.4 is hydrogen
and Y is O.
38. The compound according to claim 1 wherein R.sub.4 is
.alpha.'-hydroxy and Y is O.
39. The compound according to claim 1 wherein R.sub.4 is hydrogen
and Y is S.
40. The compound according to claim 1 wherein R.sub.4 is
.alpha.'-hydroxy and Y is S.
41. A compound of Formula (I): ##STR00100## 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; R.sub.6 is one to four substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6alkanyl, C.sub.2-6alkenyl, C.sub.1-6alkanyloxy, halogen,
hydroxy, fluoro(C.sub.1-6)alkanyl and fluoro(C.sub.1-6)alkanyloxy.
Y is O or S; Z is O, NH, N(C.sub.1-6alkanyl), N(OH),
N(OC.sub.1-6alkanyl), or N(phenyl); and enantiomers, diastereomers,
tautomers, solvates, and pharmaceutically acceptable salts
thereof.
42. A compound of Formula (I): ##STR00101## 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.1-4)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; 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, aminocarbonyl, and hydroxy; R.sub.5
is hydrogen; R.sub.6 is one to two substituents independently
selected from the group consisting of hydrogen and
C.sub.1-4alkanyl; Y is O or S; Z is O, NH, or N(OH); and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
43. The compound according to claim 26 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 compound according to claim 26 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 compound according to claim 26 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.1-13alkanyl 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.
46. A compound of Formula (I): ##STR00102## 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
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, aminocarbonyl, and hydroxy; R.sub.5
is hydrogen; R.sub.6 is one to two substituents independently
selected from the group consisting of hydrogen and methyl; Y is O
or S; Z is O or NH; and enantiomers, diastereomers, tautomers,
solvates, and pharmaceutically acceptable salts thereof.
47. The compound according to claim 31 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.
48. The compound according to claim 31 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, aminocarbonyl, and
hydroxy.
49. The compound according to claim 31 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, aminocarbonyl, and hydroxy.
50. The compound according to claim 31 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, aminocarbonyl, and hydroxy.
51. A compound of Formula (I): ##STR00103## wherein: G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadiazolyl, and pyridinyl, wherein
the phenyl and the heterocycles of G are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-4alkanylcarbonylamino and oxo; R.sub.1
is selected from the group consisting of hydrogen and ethyl;
R.sub.2 is selected from the group consisting of hydrogen and
C.sub.1-4alkanyl; 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; R.sub.3 is hydrogen,
C.sub.1-8alkanyl, C.sub.2-8alkenyl, phenyl(C.sub.1-8)alkanyl, or
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is imidazolyl,
furanyl, pyridinyl, or thienyl; R.sub.4 is one substituent selected
from the group consisting of hydrogen, methoxy, hydroxy,
hydroxycarbonyl, and aminocarbonyl; R.sub.5 is hydrogen; R.sub.6 is
hydrogen; Y is O or S; Z is O; and enantiomers, diastereomers,
tautomers, solvates, and pharmaceutically acceptable salts
thereof.
52. A compound according to claim 51 wherein R.sub.4 is hydrogen
and Y is O.
53. A compound according to claim 51 wherein R.sub.4 is
.alpha.'-hydroxy and Y is O.
54. A compound according to claim 51 wherein R.sub.4 is hydrogen
and Y is S.
55. A compound according to claim 51 wherein R.sub.4 is
.alpha.'-hydroxy and Y is S.
56. A compound of Formula (I): ##STR00104## wherein: G is
N,N-diethylaminocarbonyl, 2-methylcarbonylaminophenyl,
N--N-diethylamidino, pyridin-3-yl,
3-(S)-hydroxypyrrolidin-1-ylcarbonyl, N-ethylaminocarbonyl,
1H-tetrazol-4-yl, pyridine-4-yl, 4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
N,N-dimethylaminocarbonyl, or pyrrolidin-1-ylcarbonyl; R.sub.1 is
selected from the group consisting of hydrogen and ethyl; R.sub.2
is hydrogen or ethyl; 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; R.sub.3 is hydrogen, methyl,
3-methyl-2-butenyl, benzyl, phenethyl, or heteroarylmethyl wherein
the heteroaryl is furanyl, imidazolyl, pyridinyl, or thienyl;
R.sub.4 is one substituent and is hydrogen, methoxy, or hydroxy;
R.sub.5 is hydrogen; R.sub.6 is hydrogen; Y is O or S; Z is O; and
enantiomers, diastereomers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
57. A compound according to claim 56 wherein R.sub.4 is hydrogen
and Y is O.
58. A compound according to claim 56 wherein R.sub.4 is
.alpha.'-hydroxy and Y is O.
59. A compound according to claim 56 wherein R.sub.4 is hydrogen
and Y is S.
60. A compound according to claim 56 wherein R.sub.4 is
.alpha.'-hydroxy and Y is S.
61.-62. (canceled)
63. A composition comprising the dextrorotatory enantiomer of a
compound of claim 1 wherein said composition is substantially free
from the levorotatory isomer of said compound.
64. A composition comprising the levororotatory enantiomer of a
compound of claim 1 wherein said composition is substantially free
from the dextrorotatory isomer of said compound.
65. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 1 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
66. A veterinary composition comprising a compound, salt or solvate
according to claim 1 admixed with a veterinarily acceptable
carrier, excipient or diluent.
67. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 41 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
68. A veterinary composition comprising a compound, salt or solvate
according to claim 41 admixed with a veterinarily acceptable
carrier, excipient or diluent.
69. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 42 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
70. A veterinary composition comprising a compound, salt or solvate
according to claim 42 admixed with a veterinarily acceptable
carrier, excipient or diluent.
71. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 46 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
72. A veterinary composition comprising a compound, salt or solvate
according to claim 46 admixed with a veterinarily acceptable
carrier, excipient or diluent.
73. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 51 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
74. A veterinary composition comprising a compound, salt or solvate
according to claim 51 admixed with a veterinarily acceptable
carrier, excipient or diluent.
75. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 56 admixed with a pharmaceutically
acceptable carrier, excipient or diluent.
76. A veterinary composition comprising a compound, salt or solvate
according to claim 56 admixed with a veterinarily acceptable
carrier, excipient or diluent.
77.-80. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. application Ser.
No. 60/641,699, filed Jan. 6, 2005, which is incorporated herein 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 OF THE INVENTION
[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 OF THE INVENTION
[0013] The present invention is directed to compounds of Formula
(I) and to compositions comprising one or more compounds 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 the
C.sub.6-10aryl 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, 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--; [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
substitutents 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] R.sub.6 is one to four 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; [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] Finally, the present invention is directed to 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 OF THE INVENTION
[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, hexylene, 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,
hexylene, 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. Heteratoms 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] An embodiment of the present invention is directed to
compounds of Formula (I) wherein the structure of Formula (I) is as
defined below.
##STR00003##
[0045] The present invention is directed to analgesic and
anti-pyretic uses of compositions comprising a compound of Formula
(I):
##STR00004##
wherein: [0046] 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 the
C.sub.6-10aryl 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; [0047] 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; [0048] 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; [0049] 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;
[0050] 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 alkanloxy
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--; [0051]
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--; [0052]
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;
[0053] R.sub.6 is one to four 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; [0054] Y
is O or S; [0055] 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.
[0056] Embodiments of the present invention include compounds and
compositions comprising compounds of Formula (I) wherein,
preferably: [0057] 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; [0058] 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; [0059] 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; [0060] d) G is
--C(Z)N(R.sub.1)R.sub.2, phenyl, or a heterocycle selected from the
group consisting of tetrazolyl, oxadiazolyl, and pyridinyl, wherein
the phenyl and the heterocycles of G are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-4alkanylcarbonylamino and oxo; [0061]
e) G is N,N-diethylaminocarbonyl, 2-methylcarbonylaminophenyl,
N--N-diethylamidino, pyridin-3-yl,
3-hydroxypyrrolidin-1-ylcarbonyl, N-ethylaminocarbonyl,
1H-tetrazol-4-yl, pyridine-4-yl, 4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
N,N-dimethylaminocarbonyl, or pyrrolidin-1-ylcarbonyl; [0062] f)
R.sub.1 is a substituent selected from the group consisting of
hydrogen and C.sub.1-4alkanyl; [0063] g) R.sub.1 is selected from
the group consisting of hydrogen, methyl, ethyl, and propyl; [0064]
h) R.sub.1 is selected from the group consisting of hydrogen,
methyl, or ethyl; [0065] i) R.sub.1 is selected from the group
consisting of hydrogen and ethyl; [0066] j) 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, 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;
[0067] k) 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; [0068] l) 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; [0069] m) R.sub.2 is
selected from the group consisting of hydrogen and
C.sub.1-4alkanyl; 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; [0070] n) R.sub.2 is hydrogen
or ethyl; 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; [0071] o) 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--; [0072] p) 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; [0073] q) R.sub.3 is hydrogen, C.sub.1-8alkanyl,
C.sub.2-8alkenyl, phenyl(C.sub.1-8)alkanyl, or
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is imidazolyl,
furanyl, pyridinyl, or thienyl; [0074] r) 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; [0075] s) R.sub.3 is hydrogen,
methyl, 3-methyl-2-butenyl, benzyl, phenethyl, or heteroarylmethyl
wherein the heteroaryl is furanyl, imidazolyl, pyridinyl, or
thienyl; [0076] t) 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; [0077] u) 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, aminocarbonyl; and
hydroxy; [0078] v) 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, aminocarbonyl; and
hydroxy; [0079] w) R.sub.4 is one substituent selected from the
group consisting of hydrogen, methoxy, hydroxyl, hydroxycarbonyl,
and aminocarbonyl; [0080] x) R.sub.4 is one substituent and is
hydrogen, methoxy, or hydroxy; [0081] y) R.sub.5 is one to two
substituents independently selected from the group consisting of
hydrogen and halogen; [0082] z) R.sub.5 is hydrogen; [0083] aa)
R.sub.6 is one to four substituents independently selected from the
group consisting of hydrogen, C.sub.1-6alkanyl, C.sub.2-6alkenyl,
C.sub.1-6alkanyloxy, halogen, hydroxy, fluoro(C.sub.1-6)alkanyl and
fluoro(C.sub.1-6)alkanyloxy; [0084] bb) R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4alkanyl; [0085] cc) R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and methyl; [0086] dd) R.sub.6 is hydrogen; [0087] ee) Y
is O or S; [0088] ff) Y is O; [0089] gg) Z is O, NH,
N(C.sub.1-6alkanyl), N(OH), N(OC.sub.1-6alkanyl), or N(phenyl); hh)
Z is O, NH, or N(OH); [0090] ii) Z is O or NH; [0091] jj) Z is O;
[0092] kk) R.sub.4 is hydrogen and Y is O; [0093] ll) R.sub.4 is
.alpha.'-hydroxy and Y is O; [0094] mm) R.sub.4 is hydrogen and Y
is S; [0095] nn) R.sub.4 is .alpha.'-hydroxy and Y is S; and
combinations of a) through nn) above.
[0096] embodiment of the present invention is a compound of Formula
(I) or a composition comprising a compound of Formula (I) wherein
one embodiment of the present invention is a compound of Formula
(I) or a composition comprising a compound of Formula (I) wherein:
[0097] 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; [0098] R.sub.1 is hydrogen or
C.sub.1-4alkanyl; [0099] 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;
[0100] 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--; [0101] 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; [0102] R.sub.5 is one to two
substituents independently selected from the group consisting of
hydrogen and halogen; [0103] R.sub.6 is one to four substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6alkanyl, C.sub.2-6alkenyl, C.sub.1-6alkanyloxy, halogen,
hydroxy, fluoro(C.sub.1-6)alkanyl and fluoro(C.sub.1-6)alkanyloxy;
[0104] Y is O or S; [0105] Z is O, NH, N(C.sub.1-6alkanyl), N(OH),
N(OC.sub.1-6alkanyl), or N(phenyl); and enantiomers, diastereomers,
tautomers, solvates, and pharmaceutically acceptable salts
thereof.
[0106] Another embodiment of the present invention is a compound of
Formula (I) or a composition comprising a compound of Formula (I)
wherein: [0107] 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; [0108] R.sub.1 is selected from
the group consisting of hydrogen, methyl, ethyl, and propyl; [0109]
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; [0110] 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; [0111] 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, aminocarbonyl; and
hydroxy; [0112] R.sub.5 is hydrogen; [0113] R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and C.sub.1-4alkanyl; [0114] Y is O or S; [0115] Z is O,
NH, or N(OH); and [0116] enantiomers, diastereomers, tautomers,
solvates, and pharmaceutically acceptable salts thereof.
[0117] Another embodiment of the present invention is directed to
compounds and to compositions comprising a compound of Formula (I)
wherein: [0118] 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; R.sub.1 is hydrogen, methyl,
or ethyl; [0119] 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 [0120] 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; [0121] 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; [0122] 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,
aminocarbonyl; and hydroxy; [0123] R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and methyl; [0124] Y is O or S; [0125] Z is O or NH; and
[0126] enantiomers, diasteromers, tautomers, solvates, and
pharmaceutically acceptable salts thereof.
[0127] Another embodiment of the present invention is a compound of
Formula (I) or a composition comprising a compound of Formula (I)
wherein: [0128] 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; [0129] R.sub.1 is hydrogen, methyl, or ethyl;
[0130] 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; [0131]
or R.sub.1 and R.sub.2 taken together with the nitrogen to which
they are attached form a pyrrolidinyl or piperidinyl ring; [0132]
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--;
[0133] 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, aminocarbonyl; and hydroxy; [0134]
R.sub.5 is hydrogen; [0135] R.sub.6 is one to two substituents
independently selected from the group consisting of hydrogen and
methyl; [0136] Y is O or S; [0137] Z is O or NH; and enantiomers,
diastereomers, tautomers, solvates, and pharmaceutically acceptable
salts thereof.
[0138] Another embodiment of the present invention is directed to
compounds and to compositions comprising a compound of Formula (I)
wherein: [0139] 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; [0140] R.sub.1 is hydrogen, methyl, or ethyl;
[0141] 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; [0142] 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; [0143] 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; [0144] 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, aminocarbonyl; and
hydroxy; [0145] R.sub.5 is hydrogen; [0146] R.sub.6 is one to two
substituents independently selected from the group consisting of
hydrogen and methyl; [0147] Y is O or S; and [0148] Z is O or
NH.
[0149] Another embodiment of the present invention is directed to
compounds and to compositions comprising a compound of Formula (I)
wherein: [0150] 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; [0151] R.sub.1 is hydrogen, methyl, or ethyl;
[0152] 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; [0153] 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; [0154]
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, aminocarbonyl; and hydroxy: [0155]
R.sub.5 is hydrogen; [0156] R.sub.6 is one to two substituents
independently selected from the group consisting of hydrogen and
methyl; [0157] Y is O or S; and [0158] Z is O or NH.
[0159] Another embodiment of the present invention is directed to
compounds and to compositions comprising a compound of Formula (I)
wherein: [0160] 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; [0161] R.sub.1 is hydrogen, methyl, or ethyl;
[0162] 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; [0163] 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; [0164]
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; [0165]
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, aminocarbonyl; and hydroxy; [0166] R.sub.5 is
hydrogen; [0167] R.sub.6 is one to two substituents independently
selected from the group consisting of hydrogen and methyl; [0168] Y
is O or S; and [0169] Z is O or NH.
[0170] Another embodiment of the present invention is directed to
compounds of Formula (I) and to compostions comprising compounds of
Formula (I) wherein: [0171] G is --C(Z)N(R.sub.1)R.sub.2, phenyl,
or a heterocycle selected from the group consisting of tetrazolyl,
oxadiazolyl, and pyridinyl, wherein the phenyl and the heterocycles
of G are optionally substituted with one to three substituents
independently selected from the group consisting of
C.sub.1-4alkanylcarbonylamino and oxo; [0172] R.sub.1 is selected
from the group consisting of hydrogen and ethyl; [0173] R.sub.2 is
selected from the group consisting of hydrogen and
C.sub.1-4alkanyl; [0174] 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; [0175] R.sub.3 is hydrogen,
C.sub.1-8alkanyl, C.sub.2-8alkenyl, phenyl(C.sub.1-8)alkanyl, or
heteroaryl(C.sub.1-8)alkanyl wherein the heteroaryl is imidazolyl,
furanyl, pyridinyl, or thienyl; [0176] R.sub.4 is one substituent
selected from the group consisting of hydrogen, methoxy, hydroxy,
hydroxycarbonyl, and aminocarbonyl; [0177] R.sub.5 is hydrogen;
[0178] R.sub.6 is hydrogen; [0179] Y is O or S; and [0180] Z is
O.
[0181] Another embodiment of the present invention is directed to
compounds of Formula (I) and to compostions comprising compounds of
Formula (I) wherein: [0182] G is N,N-diethylaminocarbonyl,
2-methylcarbonylaminophenyl, N--N-diethylamidino, pyridin-3-yl,
3-(S)-hydroxypyrrolidin-1-ylcarbonyl, N-ethylaminocarbonyl,
1H-tetrazol-4-yl, pyridine-4-yl, 4H-[1,2,4]-oxadiazol-5-oxo-3-yl,
N,N-dimethylaminocarbonyl, or pyrrolidin-1-ylcarbonyl; [0183]
R.sub.1 is selected from the group consisting of hydrogen and
ethyl; [0184] R.sub.2 is hydrogen or ethyl; [0185] 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;
[0186] R.sub.3 is hydrogen, methyl, 3-methyl-2-butenyl, benzyl,
phenethyl, or heteroarylmethyl wherein the heteroaryl is furanyl,
imidazolyl, pyridinyl, or thienyl; [0187] R.sub.4 is one
substituent and is hydrogen, methoxy, or hydroxyl; [0188] R.sub.5
is hydrogen; [0189] R.sub.6 is hydrogen; [0190] Y is O or S; and
[0191] Z is O.
[0192] Still further embodiments of the invention relate to
compounds of Formula (I) and to compositions containing compounds
of Formula (I) that are: [0193]
10-(1-Benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic
acid diethylamide; [0194]
10-(1-Benzylpiperidin-4-yl)-10H-phenoxazine-3,6-dicarboxylic acid
6-amide 3-diethylamide; [0195]
10-(1-Benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic
acid dimethylamide; [0196]
3-[10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2-
,4]oxadiazol-5-one; [0197]
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0198]
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne; [0199]
3-[10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl-
]-4H-[1,2,4]oxadiazol-5-one; [0200]
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoth-
iazine; [0201]
10-(1-Pyridin-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0202]
N-[2-(6-Hydroxy-10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide;
[0203]
10-(1-Benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxyli-
c acid diethylamide; [0204]
10-Piperidin-4-yl-7-pyridin-3-yl-10H-phenoxazin-4-ol; [0205]
3-[10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]-
oxadiazol-5-one; [0206]
10-Piperidin-4-yl-10H-phenoxazine-3,6-dicarboxylic acid 6-amide
3-diethylamide; [0207]
N-[2-(10-Piperidin-4-yl-10H-phenothiazin-3-yl)-phenyl]-acetamide;
[0208]
N-[2-(10-Piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide;
[0209]
10-(1-Benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid amide; [0210]
10-[1-(1H-Imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxyl-
ic acid diethylamide; [0211]
10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide; [0212]
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide; [0213]
10-[1-(3-Methyl-but-2-enyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxylic
acid diethylamide; [0214]
10-Piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine; [0215]
N,N-Diethyl-10-piperidin-4-yl-10H-phenoxazine-3-carboxamidine;
[0216]
N-(2-{10-[1-(3-Methyl-but-2-enyl)-piperidin-4-yl]-10H-phenothiazin-3-yl}--
phenyl)-acetamide; [0217]
[10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-hydro-
xypyrrolidin-1-yl)-methanone; [0218]
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)--
10H-phenoxazin-3-yl]-methanone; [0219]
10-Piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine; [0220]
10-(1-Benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid; [0221]
N-{2-[10-(1-Methyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-phenyl}--
acetamide; [0222]
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxa-
zine; [0223]
(3-Hydroxypyrrolidin-1-yl)-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H--
phenothiazin-3-yl]-methanone; [0224]
N-(2-{10-[1-(1H-Imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazin-3-yl}-
-phenyl)-acetamide; [0225]
N,N-Diethyl-10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carb-
oxamidine; [0226]
N-{2-[10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-phe-
nyl}-acetamide; [0227]
N,N-Diethyl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-ca-
rboxamidine; [0228]
3-(10-Piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one;
[0229]
N,N-Diethyl-10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazine-3-carb-
oxamidine; [0230]
10-(1-Thiazol-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0231]
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide; [0232]
3-Pyridin-3-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-
; [0233]
10-(1-Benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxyl-
ic acid dimethylamide; [0234]
10-[1-(Imino-phenyl-methyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxylic
acid diethylamide; [0235]
N-{2-[10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}-acetamide-
; [0236]
3-[10-(1-Phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4-
]oxadiazol-5-one; [0237]
10-Piperidin-4-yl-10H-phenoxazine-3-carbonitrile; [0238]
[10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-Hydroxyp-
yrrolidin-1-yl)-methanone; [0239]
10-Piperidin-4-yl-3-pyridin-3-yl-10H-phenothiazine; [0240]
10-(1-Phenethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine;
[0241]
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenothi-
azine; [0242] 10-Piperidin-4-yl-7-pyridin-4-yl-10H-phenoxazin-4-ol;
[0243] 10-Piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine; [0244]
N-{2-[10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-ph-
enyl}-acetamide; [0245]
N-{2-[10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-pheny-
l}-acetamide; [0246]
6-Methoxy-10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine; [0247]
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0248]
10-[1-(1H-Imidazol-2-ylmethyl)-piperidin-4-yl]-3-(1H-tetrazol-5-yl)-10H-p-
henoxazine; [0249] 10-Piperidin-4-yl-10H-phenoxazine-3-carboxylic
acid amide; [0250]
10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide; [0251]
N,N-Diethyl-10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carboxamidin-
e; [0252]
10-(1-Benzyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine; [0253]
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
methyl ester; [0254]
10-(1-Phenethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide; [0255]
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid;
[0256] 10-(1-Methyl-piperidin-4-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide; [0257]
3-Pyridin-4-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine;
[0258]
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxaz-
ine; [0259]
10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid;
[0260]
(3-(S)-Hydroxypyrrolidin-1-yl)-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-me-
thanone; [0261]
N-{2-[10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phen-
yl}-acetamide; [0262] 3-Bromo-10-piperidin-4-yl-10H-phenothiazine;
[0263]
[10-(1-Methyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-pyrrolidin-1-yl-meth-
anone; [0264]
3-Bromo-10-(1-phenethyl-piperidin-4-yl)-10H-phenothiazine; [0265]
10-(1-Benzyl-piperidin-4-yl)-3-chloro-10H-phenoxazine;
[0266] 10-Piperidin-4-yl-10H-phenothiazine-3-carbonitrile; [0267]
10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide; [0268]
3-Chloro-6-methoxy-10-piperidin-4-yl-10H-phenoxazine; [0269]
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenothiazine;
[0270] 10-(1-Benzyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine;
[0271]
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine;
[0272] 10-Piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenothiazine;
[0273]
N-{2-[10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide; [0274]
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid;
[0275]
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-methyl-piperidin-4-yl)-10H-phenoxaz-
in-3-yl]-methanone; [0276]
(3-Hydroxypyrrolidin-1-yl)-[10-(1-methylpiperidin-4-yl)-10H-phenothiazin--
3-yl]-methanone; [0277]
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-phenethyl-piperidin-4-yl)-10H-pheno-
xazin-3-yl]-methanone; [0278]
(3-Hydroxypyrrolidin-1-yl)-[10-(1-phenethyl-piperidin-4-yl)-10H-phenothia-
zin-3-yl]-methanone; [0279]
3-Pyridin-4-yl-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine;
[0280]
10-(1-Methyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazin-
e; [0281] 3-Bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine;
[0282]
3-Pyridin-3-yl-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine;
[0283]
N-{2-[10-(1-Phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}-
-acetamide; [0284]
10-(1-Methyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile;
[0285]
10-(1-Benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxyl-
ic acid; [0286]
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine;
[0287]
3-Pyridin-3-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine;
[0288]
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxaz-
ine; [0289] 7-Chloro-10-piperidin-4-yl-10H-phenoxazin-4-ol; or
[0290] 10-(1-Benzoyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide.
[0291] 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).
[0292] 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##
[0293] 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##
[0294] 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.
[0295] 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.
[0296] 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.
[0297] 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-l-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.
[0298] 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.
[0299] 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.
[0300] 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).
[0301] 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.
[0302] 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.
[0303] 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.
[0304] 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.
[0305] 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.
[0306] 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.
[0307] 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.
[0308] 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.
[0309] 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.
[0310] 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.
[0311] 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.
[0312] 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.
[0313] 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.
[0314] 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.
[0315] 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.
[0316] 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.
[0317] In regard to the use of the present compounds in treatment
of the disases 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
[0318] 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.
##STR00005##
[0319] 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, an
appropriately substituted N1-protected 4-aminopiperidine 1.1 is
condensed with an appropriately substituted O-protected phenol
(Y.dbd.O) or thiophenol (Y.dbd.S) 1.2. The protection 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. Useful phenol or thiophenol protection 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, or
trifluoromethanesulfonyloxy. Stage 1.2 includes removal 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.
[0320] 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.
[0321] 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
eample: `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).
[0322] The protective group P can be removed to obtain secondary
amines 1 as illustrated in 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 trifluoromethylcarbonyl
group may be treated with potassium carbonate in an alcoholic
solvent such as methanol to yield phenoxazines and phenothiazines
1.
[0323] 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.
[0324] The Q function in compounds 1 or 2 may be converted into
group G, which may be --C(Z)NR.sub.1R.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.
[0325] 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.
[0326] 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.
[0327] 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.
[0328] 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.
##STR00006##
[0329] 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.
##STR00007##
[0330] 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.
##STR00008##
[0331] 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 an appropriately 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 appropriately
substituted 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 as shown in stage 4.2 may result in the formation
of phenoxazines or phenothiazines 1.6.
##STR00009##
[0332] 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.
##STR00010##
[0333] 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 R.sub.6-substituted
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.
##STR00011##
[0334] 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 R.sub.6-substituted 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 phenols (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 7.3 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.
##STR00012##
[0335] 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 R.sub.6-substituted 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.
##STR00013##
[0336] Scheme 9 illustrates another synthetic approach to compounds
of formula 7.4. Displacement of X.sub.1 in appropriately
substituted compounds of formula 9.1 with appropriately substituted
compounds of formula 5.1 as shown in stage 9.1 may lead to biaryl
ethers (Y.dbd.O) and biarylthioethers (Y.dbd.S) of formula 9.2.
Appropriate X.sub.1 and X.sub.3 substituents may include halogens
and trifluoromethanesulfonyloxy. Reduction of compounds of formula
9.2 to amines of formula 9.3 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 9.3
to secondary anilines of formula 7.4 and can be accomplished via
reductive alkylation using a carbonyl compound of formula 2.5 and a
reducing agent such as sodium borohydride, sodium cyanoborohydride,
sodium triacetoxyborohydride, or tetramethylammonium
triacetoxyborohydride.
##STR00014##
Scheme 10 illustrates another synthetic approach to compounds of
formula 9.2. For construction of diaryl ethers (Y.dbd.O) and diaryl
thioethers (Y.dbd.S) of formula 9.2, appropriately substituted
2-hydroxynitrobenzenes or 2-thionitrobenzenes of formula 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.
##STR00015##
Scheme 11 illustrates another synthetic approach to compounds of
formula 1.6. Stage 11.1 depicts the conversion of appropriately
substituted 2-hydroxyanilines (Y.dbd.O) or 2-thioanilines (Y.dbd.S)
of formula 11.1 to compounds of formula 11.2, which can be
accomplished via reductive alkylation using a carbonyl compound of
formula 2.5 and a reducing agent such as sodium borohydride, sodium
cyanoborohydride, sodium triacetoxyborohydride, or
tetramethylammonium triacetoxyborohydride.
[0337] Appropriately substituted 2-hydroxyanilines or
2-thioanilines of formula 11.2 may be caused to react with an
appropriately substituted benzene of formula 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.
[0338] 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
eample: `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).
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.
[0339] In the above Schemes 1 through 11, the Q function of
compounds of formula 2 may be converted into group G, which may be
--C(Z)NR.sub.1R.sub.2, an aryl substituent, or an appropriate
heterocycle as defined herein, to give compounds of formula 3. When
the Q function of compounds of formula 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(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.
[0340] Alternatively, when the Q function of compounds of formula 2
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 amine, a base such as
DBU, and a palladium catalyst such as Herrmann's catalyst.
[0341] Instead of proceeding to compounds of formula 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 of formula 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 of formula 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.
[0342] An aryl substituent may be installed in place of the
functional group Q by coupling compounds of formula 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.
[0343] 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.
[0344] 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.
[0345] 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
[0346] AcOH=acetic acid [0347] Boc=tert-butoxycarbonyl [0348]
CH.sub.3CN=acetonitrile [0349] DIEA=N,N-diisopropyl-N-ethylamine
[0350] DME=dimethoxyethane [0351] DMF=N,N-dimethylformamide [0352]
DMSO=dimethyl sulfoxide [0353] Et=ethyl [0354] EtOAc=ethyl acetate
[0355] h=hour(s) [0356]
HATU=O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0357]
HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0358] K.sub.2CO.sub.3=potassium carbonate
[0359] Me=methyl [0360] min minute(s) [0361] rt=room temperature
[0362] TFA=trifluoroacetic acid [0363] THF=tetrahydrofuran
EXAMPLES
Example A
##STR00016## ##STR00017##
[0364] Procedure 1
3-(2-Bromo-phenoxy)-4-nitrobenzonitrile, 1a
[0365] To a solution of 3-fluoro-4-nitrobenzonitrile (6.3 g; 37.93
mmol) and 2-bromophenol (4.4 mL; 37.94 mmol) in DMF (50 mL) was
added potassium carbonate (6.29 g; 45.51 mmol). The mixture was
stirred for 5 h at rt. Water (100 mL) was added, and a precipitate
formed. The solid was separated via filtration, washed with water,
and dried to yield 11.20 g (92.5%) of
3-(2-bromo-phenoxy)-4-nitrobenzonitrile, 1a.
Procedure 2
4-Amino-3-(2-bromophenoxy)-benzonitrile, 2a
[0366] To a mixture of 3-(2-bromophenoxy)-4-nitrobenzonitrile, 1 (5
g; 15.67 mmol) in methanol (100 mL) was added tin(II) chloride
dihydrate (17.68 g; 78.36 mmol). The mixture was stirred at rt
overnight, and the solvent was removed via evaporation. Ethyl
acetate (100 mL) and 1N NaOH (100 mL) were added, and the solvents
were removed via evaporation. Ethyl acetate (200 mL) was added, and
white solid formed. The solid was removed via filtration, washed
with ethyl acetate, and the combined filtrates were evaporated. The
residue was purified via column chromatography (eluent gradient:
10% to 30% ethyl acetate in heptane) to yield 3.0 g (66%) of
4-amino-3-(2-bromophenoxy)-benzonitrile, 2a. MS m/z (MH.sup.+)
288.7/289.7.
Procedure 3
4-[2-(2-Bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxylic
acid tert-butyl ester, 3a
[0367] To a solution of 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a
(0.8 g; 2.77 mmol) and 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester (1.1 g; 5.52 mmol) in dichloroethane (80 mL) was
added sodium triacetoxyborohydride (1.17 g; 5.52 mmol) and acetic
acid (0.16 mL; 2.8 mmol). The mixture was stirred for 2 h at rt. An
additional 4 equiv of sodium triacetoxyborohydride was added, and
the mixture was heated to 90.degree. C. for 5 h. The mixture was
allowed to cool to rt, diluted with ethyl acetate (15 mL) and
treated with H.sub.2O (15 mL). The organic layer was separated,
dried over MgSO.sub.4, filtered, and evaporated. The residue was
purified via column chromatography (eluent gradient: 0 to 30% ethyl
acetate in heptane) to yield 0.6 g (46%) of
4-[2-(2-bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxylic
acid tert-butyl ester, 3a. MS m/z (MH.sup.+) 493.7.
Procedure 4
4-(3-Cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl
ester, 4a
[0368] To a suspension of sodium hydride (0.11 g; 0.74 mmol) in DMF
(5 mL) was added a solution of
4-[2-(2-bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxylic
acid tert-butyl ester, 3a (0.35 g; 0.74 mmol) in DMF (3 mL). The
mixture was heated to 120.degree. C. for 90 min and allowed to cool
to rt. The mixture was poured into ice-water and a precipitate
formed. The solid was separated via filtration, dried to yield
4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl
ester, 4a. MS m/z (M+Na) 413.9. The material was used as such for
the next reaction.
Procedure 5
4-[3-(1H-Tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a
[0369] To a solution of
4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl
ester, 4a (0.29 g; 0.68 mmol) in DMF (7 mL) were added sodium azide
(0.13 g, 2.0 mmol) and ammonium chloride (0.11 g; 2.06 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, yielding
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxyli- c
acid tert-butyl ester, 5a. MS m/z (M+Na) 456.9. The crude material
was used as such for the next reaction.
Procedure 6
10-Piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a
[0370] To a solution of
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a (0.265 g, 0.61 mmol) in DMF (2 mL) was
added a 4N hydrochloric acid solution (4 mL). The mixture was
stirred for 2 h at rt. Another 4 mL of the 4N HCl solution was
added, and the mixture was stirred for 16 h at rt. The solvent was
removed via evaporation, and the residue was purified via reverse
phase chromatography (eluent gradient: 10 to 40% acetonitrile in
water containing 0.1% TFA) to yield 0.12 g (44%) of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a as a TFA
salt. MS m/z (MH.sup.+) 335.0.
Procedure 7
10-[1-(1H-Imidazol-2-ylmethyl)-piperidin-4-yl]-3-(1H-tetrazol-5-yl)-10H-ph-
enoxazine, 7a
[0371] To a solution of the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a (40.7
mg; 0.091 mmol) and 1H-imidazole-2-carboxaldehyde (35 mg; 0.36
mmol) in dichloroethane (5 mL) was added tetramethylammonium
triacetoxyborohydride (36 mg; 0.14 mmol). The mixture was heated to
80.degree. C. for 15 hr in a sealed tube. The mixture was allowed
to cool to rt, and the solvent was removed via evaporation. The
residue was purified via reverse phase HPLC (eluent gradient: 15 to
40% acetonitrile in water containing 0.1% TFA) to yield 3.1 mg
(6.5%) of
10-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-3-(1H-tetrazol-5-yl)-10H-p-
henoxazine, 7a as a TFA salt. MS m/z (MH.sup.+) 414.9.
##STR00018##
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 8a
[0372] Using an adaptation of the method described in Procedure 7,
substituting 3-furyl carboxaldehyde for
1H-imidazole-2-carboxaldehyde and sodium triacetoxyborohydride for
tetramethylammonium triacetoxyborohydride, the title compound
10-(1-furan-3-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazi-
ne, 8a was obtained as a TFA salt after purification via reverse
phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS
m/z (MH.sup.+) 414.9.
##STR00019##
10-(1-Phenethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
9a
[0373] Using an adaptation of the method described in Procedure 7,
substituting phenyl acetaldehyde for 1H-imidazole-2-carboxaldehyde,
and sodium triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
10-(1-phenethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
9a was obtained as a TFA salt after purification via reverse phase
HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 438.9.
##STR00020##
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxa-
zine, 10a
[0374] Using an adaptation of the method described in Procedure 7,
substituting 2-pyridylcarboxaldehyde for
1H-imidazole-2-carboxaldehyde, and sodium triacetoxyborohydride for
tetramethylammonium triacetoxyborohydride, the title compound
10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoxa-
zine, 10a was obtained as a TFA salt after purification via reverse
phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS
m/z (MH.sup.+) 425.9.
##STR00021##
10-Piperidin-4-yl-10H-phenoxazine-3-carbonitrile, 11a
[0375] Using an adaptation of the method described in Procedure 6,
substituting 4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 4a for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, the title compound
10-piperidin-4-yl-10H-phenoxazine-3-carbonitrile, 11a was obtained
as a TFA salt after purification via reverse phase HPLC (eluent:
CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z (MH.sup.+)
291.9.
##STR00022##
10-Piperidin-4-yl-10H-phenoxazine-3-carboxylic acid amide, 12a
[0376] Using an adaptation of the method described in Procedure 6,
substituting 10-piperidin-4-yl-10H-phenoxazine-3-carbonitrile, 11a
for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, the title compound
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid amide, 12a was
obtained as a TFA salt after purification via reverse phase HPLC
(eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 309.9.
Example B
##STR00023##
[0377] Procedure 8
4-[3-(N-Hydroxycarbamimidoyl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 1b
[0378] To a solution of
4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl
ester, 4a (130 mg; 0.33 mmol) in ethanol (3 mL) was added ammonium
hydroxide hydrochloride (69 mg; 0.99 mmol) and potassium carbonate
(91 mg; 0.66 mmol), and the mixture was heated to reflux for 16 h.
The mixture was allowed to cool to rt, water (5 mL) was added, and
the mixture was extracted with ethyl acetate (2.times.5 mL). The
combined organic layers were dried over MgSO.sub.4, filtered, and
evaporated, yielding
4-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-piperidine-1-car-
boxylic acid tert-butyl ester, 1b. The crude material was used as
such in the next reaction. MS m/z (M+Na) 473.
Procedure 9
3-(10-Piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one,
2b
[0379] To a solution of
4-[3-(N-hydroxycarbamimidoyl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 1b (0.13 g; 0.31 mmol) in dioxane (5 mL) was
added 1,1'-carbonyldiimidazole (75 mg; 0.46 mmol), and the mixture
was stirred at 110.degree. C. for 4 hr. The mixture was allowed to
cool to rt, and treated with 4N HCl in dioxane (5 mL). The mixture
was stirred at rt for 16 hr and evaporated. The residue was
suspended in methanol, and the solid was removed via filtration.
The filtrate was purified via reverse phase HPLC (eluent gradient:
20 to 40% CH.sub.3CN in water containing 0.1% TFA) to yield 8.8 mg
(14.4%) of
3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one,
2b as a TFA salt. MS m/z (MH.sup.+) 351.1.
3-[10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]o-
xadiazol-5-one, 3b
[0380] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one,
2b for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, 3-furyl
carboxaldehyde for 1H-imidazole-2-carboxaldehyde and sodium
triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
3-[10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]-
oxadiazol-5-one, 3b was obtained as a TFA salt after purification
via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing
0.1% TFA). MS m/z (MH.sup.+) 438.8.
##STR00024##
3-[10-(1-Phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiaz-
ol-5-one, 4b
[0381] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one,
2b for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, phenyl
acetaldehyde for 1H-imidazole-2-carboxaldehyde and sodium
triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
3-[10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiaz-
ol-5-one, 4b was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 454.8.
##STR00025##
3-[10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2-
,4]oxadiazol-5-one, 5b
[0382] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one,
2b for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-thiophene carboxaldehyde for 1H-imidazole-2-carboxaldehyde and
sodium triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
3-[10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2-
,4]oxadiazol-5-one, 5b was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 446.9.
##STR00026##
3-[10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,-
4]oxadiazol-5-one, 6b
[0383] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one,
2b for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde and
sodium triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
3-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,-
4]oxadiazol-5-one, 6b was obtained as a TFA salt after purification
via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing
0.1% TFA). MS m/z (MH.sup.+) 441.9.
Example C
##STR00027##
[0384] Procedure 10
4-[3-(N,N-Diethyl-carbamimidoyl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 1c
[0385] To a solution of methylmagnesium bromide in diethyl ether
(3.0 M, 2.4 mL) under a N.sub.2 atmosphere was added dropwise a
solution of diethylamine (0.8 mL; 7.68 mmol) in diethyl ether (2
mL). The mixture was heated to reflux for 30 min and allowed to
cool to rt. A suspension of
4-(3-cyanophenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl
ester, 4a (1 g; 2.55 mmol) in diethyl ether (10 mL) was added, and
the mixture was heated to reflux for 2 h. Water (10 mL) was added,
and the organic layer was separated. The aqueous layer was
extracted with chloroform (2.times.10 mL), and the combined organic
layers were dried over MgSO.sub.4, filtered, and evaporated. The
residue was used as such for the next reaction. MS m/z (MH.sup.+)
465.0.
N,N-Diethyl-10-piperidin-4-yl-10H-phenoxazine-3-carboxamidine,
2c
[0386] Using an adaptation of the method described in Procedure 6,
substituting
4-[3-(N,N-diethylcarbamimidoyl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 1c, for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, and dioxane for DMF, the title compound
N,N-diethyl-10-piperidin-4-yl-10H-phenoxazine-3-carboxamidine, 2c
was obtained as a TFA salt after purification via reverse phase
HPLC (eluent gradient: 10 to 35% CH.sub.3CN in H.sub.2O containing
0.1% TFA). MS m/z (MH.sup.+) 365.2.
N,N-Diethyl-10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carbo-
xamidine, 3c
[0387] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
N,N-diethyl-10-piperidin-4-yl-10H-phenoxazine-3-carboxamidine, 2c
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, 3-furyl
carboxaldehyde for 1H-imidazole-2-carboxaldehyde and sodium
triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
N,N-diethyl-10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carb-
oxamidine, 3c was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 444.9.
##STR00028##
N,N-Diethyl-10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxamidi-
ne, 4c
[0388] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
N,N-diethyl-10-piperidin-4-yl-10H-phenoxazine-3-carboxamidine, 2c
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, phenyl
acetaldehyde for 1H-imidazole-2-carboxaldehyde and sodium
triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
N,N-diethyl-10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxamidi-
ne, 4c was obtained as a TFA salt after purification via reverse
phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS
m/z (MH.sup.+) 468.9.
##STR00029##
N,N-Diethyl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-ca-
rboxamidine, 5c
[0389] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
N,N-diethyl-10-piperidin-4-yl-10H-phenoxazine-3-carboxamidine, 2c
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde and
sodium triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
N,N-diethyl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-ca-
rboxamidine, 5c was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 456.
Example D
##STR00030## ##STR00031##
[0390] 4-(1-Benzyl-piperidin-4-ylamino)-3-hydroxy-benzoic acid
methyl ester, 1d
[0391] Using an adaptation of the method described in Procedure 7,
substituting 4-amino-3-hydroxy-benzoic acid methyl ester for the
TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine,
6a, 1-benzyl-piperidin-4-one for 1H-imidazole-2-carboxaldehyde, and
sodium triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
4-(1-benzyl-piperidin-4-ylamino)-3-hydroxy-benzoic acid methyl
ester, 1d was obtained.
10-(1-Benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid methyl ester, 2d
[0392] Using an adaptation of the method described in Procedure 1,
substituting 4-(1-benzyl-piperidin-4-ylamino)-3-hydroxy-benzoic
acid methyl ester, 1d for 2-bromophenol, and
1-fluoro-3-methoxy-2-nitrobenzene for 3-fluoro-4-nitrobenzonitrile,
the title compound
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid methyl ester, 2d was obtained.
Procedure 11
10-(1-Benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d
[0393] To a solution of
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid methyl ester, 2d (270 mg, 0.7 mmol) in dioxane (15 mL) was
added sodium hydroxide (31 mg, 0.77 mmol) and the mixture was
heated to reflux for 4 h. The mixture was allowed to cool to rt,
water (15 mL) was added, and the solution was acidified with 1N HCl
to pH 2. The mixture was extracted with methylene chloride, the
organic phase was separated, dried, and evaporated to yield 245 mg
(94%) of title compound
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d.
Procedure 12
10-(1-Benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 4d and
10-(1-Benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid dimethylamide, 5d
[0394] To a solution of
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d (240 mg, 0.56 mmol) in DMF was added HATU (424 mg, 1.11
mmol), N,N-diisopropyl-N-ethylamine (115 mg, 1.12 mmol), and
N,N-diethylamine (82 mg, 1.12 mmol). The mixture was allowed to
stir overnight at rt. Water (5 mL) was added, and the solution was
extracted with EtOAc. The organic layer was separated, dried, and
evaporated. The residue was purified via reverse phase HPLC
(eluent: CH.sub.3CN in water containing 0.1% TFA) to yield 93.3 mg
(28%) of
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 4d and 91.4 mg (29%) of
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid dimethylamide, 5d, both as TFA salts (presence of 5d is
presumably due to N,N-dimethylamine present in DMF). 4d: MS m/z
(MH.sup.+) 486.0; 5d: MS m/z (MH.sup.+) 458.8.
Procedure 13
10-(1-Benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 6d
[0395] To a solution of
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 4d (50 mg, 0.1 mmol) in methylene chloride (2
mL) at 0.degree. C. was added a 1M solution of boron tribromide in
methylene chloride (0.8 mL, 0.8 mmol). The mixture was allowed to
stir for 15 min at rt, followed by stirring at rt for 4 h. A
saturated NaHCO.sub.3 solution and methylene chloride were added,
and the organic phase was separated. The organic phase was dried,
filtered, and evaporated. The residue was purified via reverse
phase HPLC (eluent: CH.sub.3CN in water containing 0.1% TFA) to
yield 17 mg (29%) of title compound
10-(1-benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 6d as a TFA salt. MS m/z (MH.sup.+) 471.0.
##STR00032##
10-(1-Benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic
acid dimethylamide, 7d
[0396] Using an adaptation of the method described in Procedure 13,
substituting
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid dimethylamide, 5d for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 4d, the title compound
10-(1-benzyl-piperidin-4-yl)-6-hydroxy-10H-phenoxazine-3-carboxylic
acid dimethylamide, 7d was obtained as a TFA salt. MS m/z
(MH.sup.+) 443.9.
Example E
##STR00033## ##STR00034##
[0397] 4-Bromo-2-(2-bromophenylsulfanyl)-nitrobenzene, 1e
[0398] Using an adaptation of the method described in Procedure 1,
substituting 2-bromothiophenol for 2-bromophenol and
2-fluoro-4-bromonitrobenzene for 3-fluoro-4-nitrobenzonitrile, the
title compound 4-bromo-2-(2-bromophenylsulfanyl)-nitrobenzene, 1e
was obtained.
Procedure 14
4-Bromo-2-(2-bromophenylsulfanyl)-aniline, 2e
[0399] To a mixture of
4-bromo-2-(2-bromophenylsulfanyl)-nitrobenzene, 1e (15.56 g; 40
mmol) in acetic acid (200 mL) and methanol (400 mL) was added zinc
(15.7 g; 240 mmol) over a 30 min period. The mixture was heated to
40.degree. C. for 1 h overnight, filtered, evaporated, and dried
under vacuum overnight. The residue was suspended in 1N NaOH
solution and extracted with methylene chloride. The organic phase
was dried over MgSO.sub.4, filtered, and evaporated. The residue
was purified via flash column chromatography (eluent gradient: 0 to
10% EtOAc in heptane) to yield 14.2 g (99%) of title compound
4-bromo-2-(2-bromophenylsulfanyl)-aniline, 2e.
[4-Bromo-2-(2-bromophenylsulfanyl)-phenyl]-(1-methyl-piperidin-4-yl)-amine-
, 3e
[0400] Using an adaptation of the method described in Procedure 3,
substituting 4-bromo-2-(2-bromophenylsulfanyl)-aniline, 2e for
4-amino-3-(2-bromophenoxy)-benzonitrile, 2a, and
1-methylpiperidin-4-one for 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester, the title compound
[4-bromo-2-(2-bromophenylsulfanyl)-phenyl]-(1-methyl-piperidin-4-
-yl)-amine, 3e was obtained.
3-Bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e
[0401] Using an adaptation of the method described in Procedure 4,
substituting
[4-bromo-2-(2-bromophenylsulfanyl)-phenyl]-(1-methyl-piperidin-4-yl)-amin-
e, 3e for
4-[2-(2-bromophenoxy)-4-cyanophenylamino]-piperidine-1-carboxyli- c
acid tert-butyl ester, 3a, the title compound
3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e was
obtained. MS m/z (MH.sup.+) 375.1/377.1.
Procedure 15
3-Bromo-10-piperidin-4-yl-10H-phenothiazine, 5e
[0402] To a solution of
3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e (0.6 g,
1.6 mmol) in 1,2-dichloroethane (10 mL) was added 1-chloroethyl
chloroformate (276 .mu.L, 2.6 mmol). The mixture was heated to
reflux for 1 h, allowed to cool to rt, and evaporated. The residue
was dissolved in methanol (10 mL) and heated to reflux for 1 h.
Treatment with 1-chloroethyl chloroformate was repeated three more
times to obtain 2/3 conversion. 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 4e and 382 mg (66%) of title compound
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e. MS m/z (MH.sup.+)
401.1/403.1.
Procedure 16
10-Piperidin-4-yl-3-pyridin-3-yl-10H-phenothiazine, 6e
[0403] A mixture of 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e
(10.5 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) 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-piperidin-4-yl-3-pyridin-3-yl-10H-phenothiazine, 6e as a TFA
salt. MS m/z (MH.sup.+) 360.2.
Example F
##STR00035##
[0404] Procedure 17
3-Bromo-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
1f
[0405] To a solution of
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e (10.5 mg; 0.029
mmol) and 2-pyridyl carboxaldehyde (9.3 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.L). The mixture was stirred at rt for 18 h, quenched with
water (50 .mu.L), and lyophilized. The thus obtained crude
3-bromo-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
1f was used as such for the next reaction.
3-Pyridin-3-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
2f
[0406] Using an adaptation of the method described in Procedure 16,
substituting
3-bromo-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
1f for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, the title
compound
3-pyridin-3-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-
, 2f was obtained as a TFA salt. MS m/z (MH.sup.+) 451.2.
##STR00036##
3-Bromo-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
3f
[0407] Using an adaptation of the method described in Procedure 17,
substituting 2-thiophene carboxaldehyde for 2-pyridyl
carboxaldehyde and without adding acetic acid, the title compound
3-bromo-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
3f was obtained. MS m/z (MH.sup.+) 441.0.
##STR00037##
3-Bromo-10-(1-phenethyl-piperidin-4-yl)-10H-phenothiazine, 4f
[0408] Using an adaptation of the method described in Procedure 17,
substituting phenyl acetaldehyde for 2-pyridyl carboxaldehyde and
without adding acetic acid, the title compound
3-bromo-10-(1-phenethyl-piperidin-4-yl)-10H-phenothiazine, 4f was
obtained. MS m/z (MH.sup.+) 465.1.
Example G
##STR00038##
[0409]
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenothiazine, 1
g
[0410] Using an adaptation of the method described in Procedure 16,
substituting
3-bromo-10-(1-phenethyl-piperidin-4-yl)-10H-phenothiazine, 4f for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e the title compound
10-(1-phenethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenothiazine,
1g was obtained as a TFA salt. MS m/z (MH.sup.+) 464.2.
##STR00039##
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenothiazine,
2g
[0411] Using an adaptation of the method described in Procedure 16,
substituting
3-bromo-10-(1-phenethyl-piperidin-4-yl)-10H-phenothiazine, 4f for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e and 4-pyridyl
boronic acid for 3-pyridyl boronic acid in Procedure 16, the title
compound
10-(1-phenethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenothiazine- ,
2g was obtained as a TFA salt. MS m/z (MH.sup.+) 464.2.
##STR00040##
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenothiazine,
3g
[0412] Using an adaptation of the methods described in Procedures
16 and 17, substituting 3-furyl carboxaldehyde for 2-pyridyl
carboxaldehyde in Procedure 17, and 4-pyridyl boronic acid for
3-pyridyl boronic acid in Procedure 16, the title compound
10-(1-furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenothiazine,
3g was obtained as a TFA salt. MS m/z (MH.sup.+) 440.2.
##STR00041##
N-{2-[10-(1-Methyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-phenyl}-acetami-
de, 4g
[0413] Using an adaptation of the method described in Procedure 16,
substituting 3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine,
4e for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e and
2-acetylaminophenyl boronic acid for 3-pyridyl boronic acid, the
title compound
N-{2-[10-(1-methyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-phenyl-
}-acetamide, 4g was obtained as a TFA salt. MS m/z (MH.sup.+)
430.2.
##STR00042##
N-[2-(10-Piperidin-4-yl-10H-phenothiazin-3-yl)-phenyl]-acetamide,
5g
[0414] Using an adaptation of the method described in Procedure 16,
substituting 2-acetylaminophenyl boronic acid for 3-pyridyl boronic
acid, the title compound
N-[2-(10-piperidin-4-yl-10H-phenothiazin-3-yl)-phenyl]-acetamide,
5g was obtained as a TFA salt. MS m/z (MH.sup.+) 416.2.
##STR00043##
N-{2-[10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-phe-
nyl}-acetamide, 6g
[0415] Using an adaptation of the methods described in Procedures
16 and 17, substituting 2-acetylaminophenyl boronic acid for
3-pyridyl boronic acid in Procedure 16, the title compound
N-{2-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-phe-
nyl}-acetamide, 6g was obtained as a TFA salt. MS m/z (MH.sup.+)
507.2.
##STR00044##
N-{2-[10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-ph-
enyl}-acetamide, 7g
[0416] Using an adaptation of the methods described in Procedures
16 and 17, substituting 2-thiophene carboxaldehyde for 2-pyridyl
carboxaldehyde in Procedure 17 and 2-acetylaminophenyl boronic acid
for 3-pyridyl boronic acid in Procedure 16, the title compound
N-{2-[10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-ph-
enyl}-acetamide, 7g was obtained as a TFA salt. MS m/z (MH.sup.+)
512.2.
##STR00045##
N-(2-{10-[1-(3-Methyl-but-2-enyl)-piperidin-4-yl]-10H-phenothiazin-3-yl}--
phenyl)-acetamide, 8g
[0417] Using an adaptation of the methods described in Procedures
16 and 17, substituting 3-methyl-but-2-enal for 2-pyridyl
carboxaldehyde in Procedure 17 and 2-acetylaminophenyl boronic acid
for 3-pyridyl boronic acid in Procedure 16, the title compound
N-(2-{10-[1-(3-methyl-but-2-enyl)-piperidin-4-yl]-10H-phenothiazin-3-yl}--
phenyl)-acetamide, 8g was obtained as a TFA salt. MS m/z (MH.sup.+)
484.3.
Example H
##STR00046##
[0418] 2-(1-Benzyl-piperidin-4-ylamino)-5-chlorophenol, 1 h
[0419] Using an adaptation of the method described in Procedure 7,
substituting 2-amino-5-chlorophenol for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
1-benzyl-piperidin-4-one for 1H-imidazole-2-carboxaldehyde, and
sodium triacetoxyborohydride for tetramethylammonium
triacetoxyborohydride, the title compound
2-(1-benzyl-piperidin-4-ylamino)-5-chlorophenol, 1 h was obtained.
MS m/z (MH.sup.+) 317.
10-(1-Benzyl-piperidin-4-yl)-3-chloro-10H-phenoxazine, 2h
[0420] Using an adaptation of the method described in Procedure 1,
substituting 2-(1-benzyl-piperidin-4-ylamino)-5-chlorophenol, 1 h,
for 2-bromophenol, and 2-fluoronitrobenzene for
3-fluoro-4-nitrobenzonitrile, the title compound
10-(1-benzyl-piperidin-4-yl)-3-chloro-10H-phenoxazine, 2h was
obtained. MS m/z (MH.sup.+) 390.9.
10-(1-Benzyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine, 3h
[0421] Using an adaptation of the method described in Procedure 16,
substituting 10-(1-benzyl-piperidin-4-yl)-3-chloro-10H-phenoxazine,
2h, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, 4-pyridyl
boronic acid for 3-pyridyl boronic acid,
Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP, the title compound
10-(1-benzyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine, 3h 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.+) 434.1.
##STR00047##
10-(1-Benzyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine, 4h
[0422] Using an adaptation of the method described in Procedure 16,
substituting 10-(1-benzyl-piperidin-4-yl)-3-chloro-10H-phenoxazine,
2h, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e,
Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP, the title compound
10-(1-benzyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine, 3h 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.+) 434.1.
##STR00048##
N-{2-[10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}-acetamide-
, 5h
[0423] Using an adaptation of the method described in Procedure 16,
substituting 10-(1-benzyl-piperidin-4-yl)-3-chloro-10H-phenoxazine,
2h, for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e,
2-acetylaminophenyl boronic acid for 3-pyridyl boronic acid,
Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP, the title compound
N-{2-[10-(1-benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}-acetamide-
, 5h was obtained as a TFA salt after reverse phase HPLC
purification (eluent gradient: 20% to 40% CH.sub.3CN in water
containing 0.1% TFA). MS m/z (MH.sup.+) 490.2.
Example I
##STR00049## ##STR00050##
[0424] 4-(4-Chloro-2-hydroxyphenylamino)-piperidine-1-carboxylic
acid tert-butyl ester, 1i
[0425] Using an adaptation of the method described in Procedure 7,
substituting 2-amino-5-chlorophenol for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, and
4-oxo-piperidine-1-carboxylic acid tert-butyl ester for
1H-imidazole-2-carboxaldehyde, the title compound
4-(4-chloro-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester, 1i was obtained. MS m/z (MH.sup.+) 327.
4-(3-Chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 2i
[0426] Using an adaptation of the method described in Procedure 1,
substituting
4-(4-chloro-2-hydroxyphenylamino)-piperidine-1-carboxylic acid
tert-butyl ester, 1i, for 2-bromophenol, and 2-fluoronitrobenzene
for 3-fluoro-4-nitrobenzonitrile, the title compound
4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 2i was obtained. MS m/z (MH.sup.+) 401.
4-(3-Pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 3i
[0427] Using an adaptation of the method described in Procedure 16,
substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 2i, for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e,
Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP, the title compound
4-(3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 3i was obtained. MS m/z (MH.sup.+) 444.
10-Piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i
[0428] Using an adaptation of the method described in Procedure 6,
substituting
4-(3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 3i, for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, and a mixture of TFA in methylene
chloride for a 4N hydrochloric acid solution, the title compound
10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i was obtained
as a TFA salt after purification via reverse phase HPLC (eluent
gradient: CH.sub.3CN in water containing 0.1% TFA). MS m/z
(MH.sup.+) 344.
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine,
5i
[0429] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, 3-furyl
carboxaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethyl-ammonium
triacetoxyborohydride, and a 3:1 mixture of 1,2-dichloroethane:THF
for 100% 1,2-dichloroethane, the title compound
10-(1-furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine,
5i was obtained as a TFA salt after purification via reverse phase
HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 424.
##STR00051##
3-Pyridin-3-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine,
6i
[0430] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridyl carboxaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethyl-ammonium
triacetoxyborohydride, and a 3:1 mixture of 1,2-dichloroethane:THF
for 100% 1,2-dichloroethane, the title compound
3-pyridin-3-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine,
6i was obtained as a TFA salt after purification via reverse phase
HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 435.
##STR00052##
3-Pyridin-3-yl-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine,
7i
[0431] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-thiophene carboxaldehyde for 1H-imidazole-2-carboxaldehyde,
sodium triacetoxyborohydride for tetramethyl-ammonium
triacetoxyborohydride, and a 3:1 mixture of 1,2-dichloroethane:THF
for 100% 1,2-dichloroethane, the title compound
3-pyridin-3-yl-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine,
7i was obtained as a TFA salt after purification via reverse phase
HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 440.
##STR00053##
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine,
8i
[0432] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-3-yl-10H-phenoxazine, 4i
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, phenyl
acetaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethyl-ammonium
triacetoxyborohydride, and a 3:1 mixture of 1,2-dichloroethane:THF
for 100% 1,2-dichloroethane, the title compound
10-(1-phenethyl-piperidin-4-yl)-3-pyridin-3-yl-10H-phenoxazine, 8i
was obtained as a TFA salt after purification via reverse phase
HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 448.
Example J
##STR00054##
[0433]
4-[3-(2-Acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carboxyli-
c acid tert-butyl ester, 1j
[0434] Using an adaptation of the method described in Procedure 16,
substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 2i, for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e,
N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide
for 3-pyridyl boronic acid, Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2
for Pd(PPh.sub.3).sub.4 and a 5:1 mixture of dioxane:water for NMP,
the title compound
4-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carbox-
ylic acid tert-butyl ester, 1j was obtained.
N-[2-(10-Piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide,
2j
[0435] Using an adaptation of the method described in Procedure 6,
substituting
4-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 1j, for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, and a mixture of TFA in methylene
chloride for a 4N hydrochloric acid solution, the title compound
N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j
was obtained as a TFA salt after purification via reverse phase
HPLC (eluent gradient: CH.sub.3CN in water containing 0.1% TFA). MS
m/z (MH.sup.+) 400.
N-{2-[10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}--
acetamide, 3j
[0436] Using an adaptation of the method described in Procedure 7,
substituting
N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
3-furaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethylammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
N-{2-[10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl-
]-phenyl}-acetamide, 3j was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 480.
##STR00055##
N-{2-[10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phen-
yl}-acetamide, 4j
[0437] Using an adaptation of the method described in Procedure 7,
substituting
N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-thiophene carboxaldehyde for 1H-imidazole-2-carboxaldehyde,
sodium triacetoxyborohydride for tetramethylammonium borohydride,
and a 3:1 mixture of 1,2-dichloroethane:THF for 100%
1,2-dichloroethane, the title compound
N-{2-[10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl-
]-phenyl}-acetamide, 3j was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 496.
##STR00056##
N-{2-[10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-pheny-
l}-acetamide, 5j
[0438] Using an adaptation of the method described in Procedure 7,
substituting
N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridyl carboxaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethylammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
N-{2-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3--
yl]-phenyl}-acetamide, 5j was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 491.
##STR00057##
N-{2-[10-(1-Phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-phenyl}-acetam-
ide, 6j
[0439] Using an adaptation of the method described in Procedure 7,
substituting
N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, phenyl
acetaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethylammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
N-{2-[10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-pheny-
l}-acetamide, 6j was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 504.
##STR00058##
N-(2-{10-[1-(1H-Imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazin-3-yl}-
-phenyl)-acetamide, 7j
[0440] Using an adaptation of the method described in Procedure 7,
substituting
N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, sodium
triacetoxyborohydride for tetramethylammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
N-(2-{10-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazin-3-yl}-
-phenyl)-acetamide, 7j was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 479.9.
Example K
##STR00059##
[0441] 4-(3-Pyridin-4-yl-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1k
[0442] Using an adaptation of the method described in Procedure 16,
substituting 4-(3-chloro-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 2i, for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, 4-pyridyl boronic
acid for 3-pyridyl boronic acid,
Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP, the title compound
4-(3-pyridin-4-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 1k was obtained. MS m/z (MH.sup.+) 444.
10-Piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k
[0443] Using an adaptation of the method described in Procedure 6,
substituting
4-(3-pyridin-4-yl-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 1k, for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, and a mixture of TFA in methylene
chloride for a 4N hydrochloric acid solution, the title compound
10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k, was obtained
as a TFA salt after purification via reverse phase HPLC (eluent
gradient: CH.sub.3CN in water containing 0.1% TFA). MS m/z
(MH.sup.+) 344.
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine,
3k
[0444] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
3-furaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethyl-ammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
10-(1-furan-3-ylmethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenox-
azine, 3k was obtained as a TFA salt after purification via reverse
phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS
m/z (MH.sup.+) 424.
##STR00060##
3-Pyridin-4-yl-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine,
4k
[0445] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-thiophene carboxaldehyde for 1H-imidazole-2-carboxaldehyde,
sodium triacetoxyborohydride for tetramethyl-ammonium borohydride,
and a 3:1 mixture of 1,2-dichloroethane:THF for 100%
1,2-dichloroethane, the title compound
3-pyridin-4-yl-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phe-
noxazine, 4k was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 440.
##STR00061##
3-Pyridin-4-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine,
5k
[0446] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridyl carboxaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethyl-ammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
3-pyridin-4-yl-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phen-
oxazine, 5k was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 435.
##STR00062##
10-(1-Phenethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine,
6k
[0447] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 2k
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, phenyl
acetaldehyde for 1H-imidazole-2-carboxaldehyde, sodium
triacetoxyborohydride for tetramethyl-ammonium borohydride, and a
3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane,
the title compound
10-(1-phenethyl-piperidin-4-yl)-3-pyridin-4-yl-10H-phenoxazine, 6k
was obtained as a TFA salt after purification via reverse phase
HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1% TFA). MS m/z
(MH.sup.+) 448.
Example L
##STR00063## ##STR00064##
[0448] Procedure 18
3-Amino-2-hydroxybenzoic acid methyl ester, 11
[0449] To a solution of 2-hydroxy-3-nitrobenzoic acid methyl ester
(5 g, 25.4 mmol) in ethanol (40 mL) was added 10% palladium on
carbon (0.5 g), and the mixture was hydrogenated for 2 h. The
catalyst was removed via filtration and the solvent was removed via
evaporation, yielding 4.17 g (88%) of title compound
3-amino-2-hydroxybenzoic acid methyl ester, 11.
3-(1-Benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid methyl ester,
2l
[0450] Using an adaptation of the method described in Procedure 3,
substituting 3-amino-2-hydroxybenzoic acid methyl ester, 1l for
4-amino-3-(2-bromophenoxy)-benzonitrile, 2a,
1-benzylpiperidin-4-one for 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester, and tetramethylammonium triacetoxyborohydride for
sodium triacetoxyborohydride, the title compound
3-(1-benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid methyl ester,
2l was obtained.
10-(1-Benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxyli-
c acid methyl ester, 3l
[0451] Using an adaptation of the method described in Procedure 1,
substituting 3-(1-benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid
methyl ester, 2l for 2-bromophenol, and
N,N-diethyl-4-fluoro-3-nitrobenzamide for
3-fluoro-4-nitrobenzonitrile, the title compound
10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxyl-
ic acid methyl ester, 3l was obtained.
Procedure 19
10-(1-Benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxyli-
c acid, 4l
[0452] To a solution of
10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxyl-
ic acid methyl ester, 3l (2.92 g, 5.7 mmol) in methanol (10 mL) was
added a 1N sodium hydroxide solution (5 mL), and the mixture was
heated to 50.degree. C. for 30 min. The mixture was allowed to cool
to rt, the solvent was evaporated, and the residue was purified via
reverse phase HPLC (eluent: CH.sub.3CN in water containing 0.1%
TFA), yielding title compound
10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-
-carboxylic acid, 4l, as a TFA salt. MS m/z (MH.sup.+) 500.1
10-(1-Benzylpiperidin-4-yl)-10H-phenoxazine-3,6-dicarboxylic acid
6-amide 3-diethylamide, 5l
[0453] Using an adaptation of the method described in Procedure 12,
substituting the TFA salt of
10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxyl-
ic acid, 4l for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d, ammonia (0.5 M solution in dioxane) for N,N-diethylamine,
and HBTU for HATU, the title compound
10-(1-benzylpiperidin-4-yl)-10H-phenoxazine-3,6-dicarboxylic acid
6-amide 3-diethylamide, 5l 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.+) 499.1.
10-Piperidin-4-yl-10H-phenoxazine-3,6-dicarboxylic acid 6-amide
3-diethylamide, 6l
[0454] Using an adaptation of the method described in Procedure 18,
substituting the TFA salt of
10-(1-benzylpiperidin-4-yl)-10H-phenoxazine-3,6-dicarboxylic acid
6-amide 3-diethylamide, 5l for 2-hydroxy-3-nitrobenzoic acid methyl
ester, palladium hydroxide for palladium on carbon and in the
presence of acetic acid, the title compound
10-piperidin-4-yl-10H-phenoxazine-3,6-dicarboxylic acid 6-amide
3-diethylamide, 61 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.+) 409.
##STR00065##
10-(1-Benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid, 7l
[0455] Using an adaptation of the method described in Procedures 1
and 19, substituting
3-(1-benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid methyl ester,
2l for 2-bromophenol, 5-bromo-2-fluoro-nitrobenzene for
3-fluoro-4-nitrobenzonitrile, and dimethyl sulfoxide for dimethyl
formamide in Procedure 1, and substituting dimethyl sulfoxide for
metyhanol in Procedure 19, the title compound
10-(1-benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid, 7l 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.+) 478.9/480.
##STR00066##
10-(1-Benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid amide, 8l
[0456] Using an adaptation of the method described in Procedure 12,
substituting the TFA salt of
10-(1-benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid, 7l for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxyli-
c acid, 3d, ammonia (0.5 M solution in dioxane) for
N,N-diethylamine, and HBTU for HATU, the title compound
10-(1-benzyl-piperidin-4-yl)-7-bromo-10H-phenoxazine-4-carboxylic
acid amide, 8l 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.+) 477.6/479.
Example M
##STR00067##
[0457] Procedure 20
[10-(1-Methyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-pyrrolidin-1-yl-metha-
none, 1m
[0458] To a solution of
3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e (19 mg,
0.05 mmol) in THF (0.3 mL) was added pyrrolidine (12 .mu.L, 0.15
mmol), Mo(CO).sub.6 (13 mg, 0.05 mmol), Herrmann's catalyst (2.3
mg, 0.0025 mmol), and DBU (22 .mu.L, 0.15 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-(1-methyl-piperidin-4-yl)-10H-phenothiazin-3-yl]-pyrrolidin-1-yl-meth-
anone, 1m as a TFA salt. MS m/z (MH.sup.+) 394.2.
##STR00068##
10-(1-Methyl-piperidin-4-yl)-10H-phenothiazine-3-carboxylic acid
ethylamide, 2m
[0459] Using an adaptation of the method described in Procedure 20,
substituting ethylamine for pyrrolidine, the title compound
10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carboxylic acid
ethylamide, 2m was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing 0.1%
TFA). MS m/z (MH.sup.+) 368.2.
##STR00069##
(3-Hydroxypyrrolidin-1-yl)-[10-(1-methylpiperidin-4-yl)-10H-phenothiazin--
3-yl]-methanone, 3m
[0460] Using an adaptation of the method described in Procedure 20,
substituting 3-hydroxypyrrolidine for pyrrolidine, the title
compound
(3-hydroxypyrrolidin-1-yl)-[10-(1-methylpiperidin-4-yl)-10H-phenothiazin--
3-yl]-methanone, 3m was obtained as a TFA salt after purification
via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing
0.1% TFA). MS m/z (MH.sup.+) 410.2.
##STR00070##
10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide, 4m
[0461] Using an adaptation of the method described in Procedure 20,
substituting
3-bromo-10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
3f for 3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e
and ethylamine for pyrrolidine, the title compound
10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carboxylic
acid ethylamide, 4m was obtained as a TFA salt after purification
via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O containing
0.1% TFA). MS m/z (MH.sup.+) 450.1.
##STR00071##
(3-Hydroxypyrrolidin-1-yl)-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H--
phenothiazin-3-yl]-methanone, 5m
[0462] Using an adaptation of the method described in Procedure 20,
substituting
3-bromo-10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine,
1f for 3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e
and 3-hydroxypyrrolidine for pyrrolidine, the title compound
(3-hydroxypyrrolidin-1-yl)-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H--
phenothiazin-3-yl]-methanone, 5m was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 487.2.
##STR00072##
(3-Hydroxypyrrolidin-1-yl)-[10-(1-phenethyl-piperidin-4-yl)-10H-phenothia-
zin-3-yl]-methanone, 6m
[0463] Using an adaptation of the method described in Procedure 20,
substituting
3-bromo-10-(1-phenethyl-piperidin-4-yl)-10H-phenothiazine, 4f for
3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine, 4e and
3-hydroxypyrrolidine for pyrrolidine, the title compound
(3-hydroxypyrrolidin-1-yl)-[10-(1-phenethyl-piperidin-4-yl)-10H-phenothia-
zin-3-yl]-methanone, 6m was obtained as a TFA salt after
purification via reverse phase HPLC (eluent: CH.sub.3CN in H.sub.2O
containing 0.1% TFA). MS m/z (MH.sup.+) 500.2.
Example N
##STR00073##
[0464] Procedure 21
10-Piperidin-4-yl-10H-phenothiazine-3-carbonitrile, 1n
[0465] To a solution of
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e (120 mg, 0.33 mmol)
in DMF (1.5 mL) was added zinc cyanide (39 mg, 0.33 mmol) and
tetrakistriphenylphosphine palladium (19 mg, 0.0165 mmol), the
solution was purged with nitrogen, and the mixture was heated in
the microwave for 6 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-piperidin-4-yl-10H-phenothiazine-3-carbonitrile, 1 n as a TFA
salt. MS m/z (MH.sup.+) 308.1.
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile,
2n
[0466] Using an adaptation of the method described in Procedure 7,
substituting 10-piperidin-4-yl-10H-phenothiazine-3-carbonitrile, 1n
for the TFA salt of
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridyl carboxaldehyde for 1H-imidazole-2-carboxaldehyde, and
sodium triacetoxyborohydride for tetramethyl-ammonium borohydride,
the title compound
10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile-
, 2n (MS m/z (MH.sup.+) 399.2). The material was used as such for
the next reaction.
Procedure 22
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenothi-
azine, 3n
[0467] To a solution of
10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile-
, 2n (79.7 mg, 0.2 mmol) in dimethoxyethane was added
trimethylsilyl azide (0.092 g, 0.8 mmol) and dibutyltin oxide (10
mg, 0.04 mmol), 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-(1-pyridin-2-ylmethyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenoth-
iazine, 3n as a TFA salt. MS m/z (MH.sup.+) 442.2.
##STR00074##
10-Piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenothiazine, 4n
[0468] Using an adaptation of the method described in Procedure 22,
substituting 10-piperidin-4-yl-10H-phenothiazine-3-carbonitrile, 1n
for
10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile-
, 2n, the title compound
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenothiazine, 4n was
obtained as a TFA salt. MS m/z (MH.sup.+) 351.1.
Example O
##STR00075##
[0469]
10-(1-Methyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile,
1o
[0470] Using an adaptation of the method described in Procedure 21,
substituting 3-bromo-10-(1-methylpiperidin-4-yl)-10H-phenothiazine,
4e for 3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, the title
compound
10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile, 1o
was obtained as a TFA salt. MS m/z (MH.sup.+) 322.1.
10-(1-Methyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine,
2o
[0471] Using an adaptation of the method described in Procedure 22,
substituting
10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile, 10
for
10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile-
, 2n, the title compound
10-(1-methyl-piperidin-4-yl)-3-(1H-tetrazol-5-yl)-10H-phenothiazine,
was obtained as a TFA salt. MS m/z (MH.sup.+) 365.1.
##STR00076##
N,N-Diethyl-10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carboxamidin-
e, 3o
[0472] Using an adaptation of the method described in Procedure 10,
substituting
10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carbonitrile, 1o
for 4-(3-cyano-phenoxazin-10-yl)-piperidine-1-carboxylic acid
tert-butyl ester, 4a, the title compound
N,N-diethyl-10-(1-methyl-piperidin-4-yl)-10H-phenothiazine-3-carboxamidin-
e, 3o 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.+) 395.2.
Example P
##STR00077##
[0473]
4-(3-Chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p
[0474] Using an adaptation of the method described in Procedure 1,
substituting
4-(4-chloro-2-hydroxyphenylamino)-piperidine-1-carboxylic acid
tert-butyl ester, 1i, for 2-bromophenol, and
6-fluoro-2-methoxynitrobenzene for 3-fluoro-4-nitrobenzonitrile,
the title compound
4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p was obtained.
4-(6-Methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 2p
[0475] Using an adaptation of the method described in Procedure 16,
substituting
4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p, for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e,
Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP, the title compound
4-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 2p was obtained. MS m/z (MH.sup.+) 474.
10-Piperidin-4-yl-7-pyridin-3-yl-10H-phenoxazin-4-ol, 3p
[0476] Using an adaptation of the method described in Procedure 13,
substituting
4-(6-methoxy-3-pyridin-3-yl-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 2p, for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 4d, the title compound
10-piperidin-4-yl-7-pyridin-3-yl-10H-phenoxazin-4-ol, 3p 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.+) 359.9.
##STR00078##
10-Piperidin-4-yl-7-pyridin-4-yl-10H-phenoxazin-4-ol, 4p and
6-Methoxy-10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 5p
[0477] Using an adaptation of the methods described in Procedures
16 and 13, substituting
4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p, for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e, 4-pyridyl boronic
acid for 3-pyridyl boronic acid,
Cp.sub.2Fe(PtBU.sub.2).sub.2PdCl.sub.2 for Pd(PPh.sub.3).sub.4 and
a 5:1 mixture of dioxane:water for NMP in Procedure 16, a mixture
of title compounds
10-piperidin-4-yl-7-pyridin-4-yl-10H-phenoxazin-4-ol, 4p and
6-methoxy-10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 5p, was
obtained. Compounds 4p and 5p were separated via reverse phase HPLC
(eluent: CH.sub.3CN in water containing 0.1% TFA) to yield pure
10-piperidin-4-yl-7-pyridin-4-yl-10H-phenoxazin-4-ol, 4p (first
eluting) and
6-methoxy-10-piperidin-4-yl-3-pyridin-4-yl-10H-phenoxazine, 5p
(second eluting) as TFA salts. 4p: MS m/z (MH.sup.+) 360; 5p: MS
m/z (MH.sup.+) 374.
##STR00079##
N-[2-(6-Hydroxy-10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide,
6p
[0478] Using an adaptation of the methods described in Procedures
16 and 13, substituting
4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p, for
3-bromo-10-piperidin-4-yl-10H-phenothiazine, 5e,
N-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide
for 3-pyridyl boronic acid, Cp.sub.2Fe(PtBu.sub.2).sub.2PdCl.sub.2
for Pd(PPh.sub.3).sub.4 and a 5:1 mixture of dioxane:water for NMP
in Procedure 16, the title compound
N-[2-(6-hydroxy-10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide,
6p 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.+) 416.
##STR00080##
3-Chloro-6-methoxy-10-piperidin-4-yl-10H-phenoxazine, 7p
[0479] Using an adaptation of the method described in Procedure 6,
substituting
4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p, for
4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic
acid tert-butyl ester, 5a, and a mixture of TFA in methylene
chloride for a 4N hydrochloric acid solution, the title compound
3-chloro-6-methoxy-10-piperidin-4-yl-10H-phenoxazine, 7p was
obtained as a TFA salt after purification via reverse phase HPLC
(eluent gradient: CH.sub.3CN in water containing 0.1% TFA). MS m/z
(MH.sup.+) 330.9.
##STR00081##
7-Chloro-10-piperidin-4-yl-10H-phenoxazin-4-ol, 8p
[0480] Using an adaptation of the method described in Procedure 13,
substituting
4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic
acid tert-butyl ester, 1p, for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid diethylamide, 4d, the title compound
7-chloro-10-piperidin-4-yl-10H-phenoxazin-4-ol, 8p 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.+)
316.8.
Example Q
##STR00082##
[0481] 3-Hydroxy-4-(1-methyl-piperidin-4-ylamino)-benzoic acid
methyl ester, 1q
[0482] Using an adaptation of the method described in Procedure 3,
substituting 4-amino-3-hydroxybenzoic acid methyl ester for
4-amino-3-(2-bromophenoxy)-benzonitrile and
1-methyl-piperidin-4-one for 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester, the title compound
3-hydroxy-4-(1-methyl-piperidin-4-ylamino)-benzoic acid methyl
ester, 1q was obtained.
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
methyl ester, 2q
[0483] Using an adaptation of the method described in Procedure 1,
substituting 3-hydroxy-4-(1-methyl-piperidin-4-ylamino)-benzoic
acid methyl ester, 1q for 2-bromophenol and 2-fluoronitrobenzene
for 3-fluoro-4-nitrobenzonitrile, the title compound
10-(1-methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
methyl ester, 2q 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.+) 338.9.
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid,
3q
[0484] Using an adaptation of the method described in Procedure 11,
substituting
10-(1-methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
methyl ester, 2q for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid methyl ester, 2d, and THF for dioxane, the title compound
10-(1-methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid, 3q
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.+) 325.2.
10-(1-Methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 4q
[0485] Using an adaptation of the method described in Procedure 12,
substituting the TFA salt of
10-(1-methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid, 3q
for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d, and HBTU for HATU, the title compound
10-(1-methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 4q 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.+) 380.2.
##STR00083##
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-methyl-piperidin-4-yl)-10H-phenoxaz-
in-3-yl]-methanone, 5q
[0486] Using an adaptation of the method described in Procedure 12,
substituting the TFA salt of
10-(1-methyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid, 3q
for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d, 3-(S)-hydroxypyrrolidine for N,N-diethylamine, and HBTU
for HATU, the title compound
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-methyl-piperidin-4-yl)-10H-phenoxaz-
in-3-yl]-methanone, 5q 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.+) 394.2.
Example R
##STR00084## ##STR00085##
[0487] 10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid methyl ester, 1r
[0488] Using an adaptation of the method described in Procedure 1,
substituting 4-(1-benzyl-piperidin-4-ylamino)-3-hydroxy-benzoic
acid methyl ester, 1d for 2-bromophenol and 2-fluoronitrobenzene
for 3-fluoro-4-nitrobenzonitrile, the title compound
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
methyl ester, 1r was obtained as a TFA salt after purification via
reverse phase HPLC (eluent: CH.sub.3CN in water containing 0.1%
TFA).
10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid,
2r
[0489] Using an adaptation of the method described in Procedure 11,
substituting the TFA salt of
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
methyl ester, 1r for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid methyl ester, 2d, and methanol for dioxane, the title compound
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid, 2r
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.+) 401.1.
10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 3r
[0490] Using an adaptation of the method described in Procedure 12,
substituting the TFA salt of
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid, 2r
for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d, and HBTU for HATU, the title compound
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 3r 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.+) 456.3.
10-Piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r
[0491] Using an adaptation of the method described in Procedure 18,
substituting the TFA salt of
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 3r for 2-hydroxy-3-nitrobenzoic acid methyl ester,
and in the presence of 1N HCl, the title compound
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r 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.+) 366.1.
10-(1-Pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 5r
[0492] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-(1-pyridin-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 5r 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.+) 457.1.
##STR00086##
10-(1-Pyridin-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 6r
[0493] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
3-pyridylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-(1-pyridin-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 6r 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.+) 457.1.
##STR00087##
10-[1-(1H-Imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxyl-
ic acid diethylamide, 7r
[0494] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxyl-
ic acid diethylamide, 7r 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.+) 446.1.
##STR00088##
10-[1-(3-Methyl-but-2-enyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxylic
acid diethylamide, 8r
[0495] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
3-methyl-but-2-enal for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-[1-(3-methyl-but-2-enyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxylic
acid diethylamide, 8r 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.+) 434.1.
##STR00089##
10-(1-Thiazol-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 9r
[0496] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
thiazole-2-carboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-(1-thiazol-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 9r 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.+) 463.
##STR00090##
10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 10r
[0497] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
3-furylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 10r 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.+) 446.1.
##STR00091##
10-(1-Phenethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 11r
[0498] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
phenylacetaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-(1-phenethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 11r 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.+) 470.1.
##STR00092##
10-(1-Thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 12r
[0499] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r for 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-thiophenecarboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic
acid diethylamide, 12r 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.+) 462.
##STR00093##
[10-(1-Benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-Hydroxypyrrolid-
in-1-yl)-methanone, 13r
[0500] Using an adaptation of the method described in Procedure 12,
substituting the TFA salt of
10-(1-benzyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid, 2r
for
10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic
acid, 3d, 3-(S)-hydroxypyrrolidine for N,N-diethylamine, and HBTU
for HATU, the title compound
[10-(1-benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-Hydroxypyrrolid-
in-1-yl)-methanone, 13r 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.+) 470.1.
##STR00094##
(3-(S)-Hydroxypyrrolidin-1-yl)-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-me-
thanone, 14r
[0501] Using an adaptation of the method described in Procedure 18,
substituting the TFA salt of
[10-(1-benzyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-Hydroxypyrrolid-
in-1-yl)-methanone, 13r for 2-hydroxy-3-nitrobenzoic acid methyl
ester, and in the presence of 1N HCl, the title compound
(3-(S)-Hydroxypyrrolidin-1-yl)-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-me-
thanone, 14r 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.+) 380.
##STR00095##
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)--
10H-phenoxazin-3-yl]-methanone, 15r
[0502] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
(3-(S)-Hydroxypyrrolidin-1-yl)-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-me-
thanone, 14r for
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
2-pyridylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-pyridin-2-ylmethyl-piperidin-4-yl)--
10H-phenoxazin-3-yl]-methanone, 15r 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.+) 471.
##STR00096##
[10-(1-Furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-Hydro-
xypyrrolidin-1-yl)-methanone, 16r
[0503] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
(3-(S)-Hydroxypyrrolidin-1-yl)-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-me-
thanone, 14r for
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
3-furylcarboxaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
[10-(1-furan-3-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-(3-(S)-Hydro-
xypyrrolidin-1-yl)-methanone, 16r 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.
##STR00097##
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-phenethyl-piperidin-4-yl)-10H-pheno-
xazin-3-yl]-methanone, 17r
[0504] Using an adaptation of the method described in Procedure 7,
substituting the TFA salt of
(3-(S)-Hydroxypyrrolidin-1-yl)-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-me-
thanone, 14r for
10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a,
phenylacetaldehyde for 1H-imidazole-2-carboxaldehyde,
tetrahydrofuran for dichloroethane, and in the presence of
N,N-diisopropyl-N-ethylamine, the title compound
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1-phenethyl-piperidin-4-yl)-10H-pheno-
xazin-3-yl]-methanone, 17r 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.+) 484.1.
Example S
##STR00098##
[0505] Procedure 23
10-[1-(Iminophenylmethyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxylic
acid diethylamide, 1s (JNJ-39020930) and
10-(1-Benzoyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 2s
[0506] To a solution of the TFA salt of
10-piperidin-4-yl-10H-phenoxazine-3-carboxylic acid diethylamide,
4r (80 mg, 0.167 mmol) in ethanol was added benzimidic acid ethyl
ester (223 mg, 1.2 mmol) N,N-diisopropyl-N-ethylamine (172 mg, 1.3
mmol), and the mixture was heated to 40.degree. C. for 24 h. The
solvent was removed via evaporation, and the residue was purified
via reverse phase HPLC yielding a mixture of target compound
10-[1-(iminophenylmethyl)-piperidin-4-yl]-10H-phenoxazine-3-carboxylic
acid diethylamide, 1s (first eluting product) as a TFA salt and
10-(1-benzoyl-piperidin-4-yl)-10H-phenoxazine-3-carboxylic acid
diethylamide, 2s (second eluting product) as a free base. 1s: MS
m/z (MH.sup.+) 469.1; 2s: MS m/z (MH.sup.+) 470.
BIOLOGICAL EXAMPLES
Rat Brain Delta Opioid Receptor Binding Assay
[0507] 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 was quantified on a LKB (Wallac) 1205 BetaPlate
liquid scintillation counter.
[0508] Analysis: The data from the scintillation counter was 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 can be
calculated using GraphPad PRISM data analysis program. The data
obtained are shown in Table 1, below.
Rat Brain Mu Opioid Receptor Binding Assay
[0509] 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 can be 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 mu 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 was
quantifed on a LKB (Wallac) 1205 BetaPlate liquid scintillation
counter.
[0510] Analysis: The data from the scintillation counter was 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. The data
obtained are shown in Table 1, below.
[.sup.35S]GTP.gamma.S Binding Assay in NG108-15 Cell Membranes
(Delta Opioid)
[0511] Methods: NG108-15 cell membranes were purchased from Applied
Cell Sciences (Rockville, Md.). 8 mg/mL of membrane protein was
suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10% sucrose.
Membranes were maintained at 4-8.degree. C. A 1 mL volume of
membranes was 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 was homogenized
twice with a Polytron, and centrifuged at 3000 rpm for 10 min. The
supernatant was then centrifuged at 18,000 rpm for 20 min. Ten mL
assay buffer was added into the pellet containing tube. The pellet
and buffer were mixed with a Polytron.
[0512] Incubation procedure: The pellet membranes (75 .mu.g/mL)
were 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) was then incubated with 0.1 nM [.sup.35S] GTP.gamma.S in
the same Tris buffer containing 100 .mu.M GDP in a total volume of
200 .mu.L. Increasing concentrations of receptor agonists were used
to stimulate [.sup.35S]-GTP.gamma.S binding. The basal binding was
tested in the absence of agonists and non-specific binding was
tested in the presence of 10 .mu.M unlabeled GTP.gamma.S. The data
were analyzed on a Packard Top Count.
Data
[0513] % of Basal=(stimulated-non specific)*100/(basal-non
specific).
EC.sub.50 value values were calculated using GraphPad Prism. The
data obtained are shown in Table 1, below.
[.sup.35S]GTP.gamma.S Binding Assays in CHO-hMOR Cell Membranes
[0514] Methods: CHO-hMOR cell membranes were purchased from
Receptor Biology, Inc. (Baltimore, Md.). About 10 mg/mL of membrane
protein was suspended in 10 mM TRIS-HCl pH 7.2, 2 mM EDTA, 10%
sucrose, and the suspension was kept on ice. A 1 mL volume of
membranes was 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 was homogenized with a Polytron
and centrifuged at 3,000 rpm for 10 min. The supernatant was then
centrifuged at 18,000 rpm for 20 min. The pellet was resuspended in
10 mL assay buffer with a Polytron. The membranes were 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) were then incubated with 0.5
nM [.sup.35S]GTP.gamma.S in the assay buffer. The basal binding was
that taking place in the absence of added test compound; this
unmodulated binding was considered as 100%, with agonist stimulated
binding rising to levels significantly above this value. A range of
concentrations of receptor agonist was used to stimulate
[.sup.35S]GTP.gamma.S binding. Both basal and non-specific binding
was tested in the absence of agonist; non-specific binding
determination included 10 .mu.M unlabeled GTP.gamma.S.
[0515] Compounds were tested for function as antagonists by
evaluating their potential to inhibit agonist-stimulated
GTP.gamma.S binding. Radioactivity was quantified on a Packard
TopCount. The following parameters were calculated:
% stimulation = ( test compound cpm - non - specific cpm ) ( basal
cpm - non - specific cpm ) . .times. 100 ##EQU00003## % inhibition
= ( % stimulation by 1 .mu.m DAMGO - % stimulation by test compound
) ( % stimulation by 1 .mu.m DAMGO - 100 ) .times. 100
##EQU00003.2##
EC.sub.50 values were calculated using GraphPad Prism. The data
obtained are shown in Table 1, below.
TABLE-US-00001 TABLE 1 delta delta mu delta mu GTP.gamma.S
GTP.gamma.S GTP.gamma.S (Ki, (Ki, EC50 Rel EC50 Compound Ex # nM)
nM) (nM) Eff (nM) 10-(1-Benzyl-piperidin-4-yl)-6- 6d 0.10
hydroxy-10H-phenoxazine-3- carboxylic acid diethylamide
10-(1-Benzylpiperidin-4-yl)-10H- 5l 0.10
phenoxazine-3,6-dicarboxylic acid 6- amide 3-diethylamide
10-(1-Benzyl-piperidin-4-yl)-6- 7d 0.17 hydroxy-10H-phenoxazine-3-
carboxylic acid dimethylamide 3-[10-(1-Thiophen-2-ylmethyl- 5b 7.08
piperidin-4-yl)-10H-phenoxazin-3-yl]- 4H-[1,2,4]oxadiazol-5-one
10-(1-Pyridin-2-ylmethyl-piperidin-4- 5r 9.63
yl)-10H-phenoxazine-3-carboxylic acid diethylamide
10-(1-Furan-3-ylmethyl-piperidin-4- 8a 15.41
yl)-3-(1H-tetrazol-5-yl)-10H- phenoxazine
3-[10-(1-Pyridin-2-ylmethyl-piperidin- 6b 17.11
4-yl)-10H-phenoxazin-3-yl]-4H- [1,2,4]oxadiazol-5-one
10-(1-Pyridin-2-ylmethyl-piperidin-4- 3n 24.47
yl)-3-(1H-tetrazol-5-yl)-10H- phenothiazine
10-(1-Pyridin-3-ylmethyl-piperidin-4- 6r 25.53
yl)-10H-phenoxazine-3-carboxylic acid diethylamide
N-[2-(6-Hydroxy-10-piperidin-4-yl- 6p 42.48
10H-phenoxazin-3-yl)-phenyl]- acetamide
10-(1-Benzyl-piperidin-4-yl)-6- 4d 42.75 methoxy-10H-phenoxazine-3-
carboxylic acid diethylamide 10-Piperidin-4-yl-7-pyridin-3-yl-10H-
3p 44.34 phenoxazin-4-ol 3-[10-(1-Furan-3-ylmethyl-piperidin- 3b
47.90 4-yl)-10H-phenoxazin-3-yl]-4H- [1,2,4]oxadiazol-5-one
10-Piperidin-4-yl-10H-phenoxazine- 6l 51.24 3,6-dicarboxylic acid
6-amide 3- diethylamide N-[2-(10-Piperidin-4-yl-10H- 5g 57.23 1966
phenothiazin-3-yl)-phenyl]- acetamide N-[2-(10-Piperidin-4-yl-10H-
2j 75.04 phenoxazin-3-yl)-phenyl]-acetamide
10-(1-Benzyl-piperidin-4-yl)-7- 8l 83.56 bromo-10H-phenoxazine-4-
carboxylic acid amide 10-[1-(1H-Imidazol-2-ylmethyl)- 7r 98.70
piperidin-4-yl]-10H-phenoxazine-3- carboxylic acid diethylamide
10-(1-Benzyl-piperidin-4-yl)-10H- 3r 100 1649
phenoxazine-3-carboxylic acid diethylamide
10-(1-Methyl-piperidin-4-yl)-10H- 4r 124 phenoxazine-3-carboxylic
acid diethylamide 10-[1-(3-Methyl-but-2-enyl)- 8r 164
piperidin-4-yl]-10H-phenoxazine-3- carboxylic acid diethylamide
10-Piperidin-4-yl-3-pyridin-3-yl-10H- 4i 164 phenoxazine
N,N-Diethyl-10-piperidin-4-yl-10H- 2c 170
phenoxazine-3-carboxamidine N-(2-{10-[1-(3-Methyl-but-2-enyl)- 8g
183 1313 piperidin-4-yl]-10H-phenothiazin-3- yl}-phenyl)-acetamide
[10-(1-Furan-3-ylmethyl-piperidin-4- 16r 189
yl)-10H-phenoxazin-3-yl]-(3-(S)- hydroxypyrrolidin-1-yl)-methanone
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1- 15r 203
pyridin-2-ylmethyl-piperidin-4-yl)- 10H-phenoxazin-3-yl]-methanone
10-Piperidin-4-yl-3-(1H-tetrazol-5- 6a 220 1352 yl)-10H-phenoxazine
10-(1-Benzyl-piperidin-4-yl)-7- 7l 223 bromo-10H-phenoxazine-4-
carboxylic acid N-{2-[10-(1-Methyl-piperidin-4-yl)- 4g 225 3717
10H-phenothiazin-3-yl]-phenyl}- acetamide
10-(1-Pyridin-2-ylmethyl-piperidin-4- 10a 227
yl)-3-(1H-tetrazol-5-yl)-10H- phenoxazine
(3-Hydroxypyrrolidin-1-yl)-[10-(1- 5m 242
pyridin-2-ylmethyl-piperidin-4-yl)-
10H-phenothiazin-3-yl]-methanone N-(2-{10-[1-(1H-Imidazol-2- 7j 249
ylmethyl)-piperidin-4-yl]-10H- phenoxazin-3-yl}-phenyl)-acetamide
N,N-Diethyl-10-(1-furan-3-ylmethyl- 3c 254
piperidin-4-yl)-10H-phenoxazine-3- carboxamidine
N-{2-[10-(1-Pyridin-2-ylmethyl- 6g 255 837
piperidin-4-yl)-10H-phenothiazin-3- yl]-phenyl}-acetamide
N,N-Diethyl-10-(1-pyridin-2- 5c 258 ylmethyl-piperidin-4-yl)-10H-
phenoxazine-3-carboxamidine 3-(10-Piperidin-4-yl-10H- 2b 259 1694
phenoxazin-3-yl)-4H- [1,2,4]oxadiazol-5-one
N,N-Diethyl-10-(1-phenethyl- 4c 266
piperidin-4-yl)-10H-phenoxazine-3- carboxamidine
10-(1-Thiazol-2-ylmethyl-piperidin-4- 9r 300
yl)-10H-phenoxazine-3-carboxylic acid diethylamide
10-(1-Methyl-piperidin-4-yl)-10H- 4q 358 >10000
phenoxazine-3-carboxylic acid diethylamide
3-Pyridin-3-yl-10-(1-pyridin-2- 2f 365 2852
ylmethyl-piperidin-4-yl)-10H- phenothiazine
10-(1-Benzyl-piperidin-4-yl)-6- 5d 374 methoxy-10H-phenoxazine-3-
carboxylic acid dimethylamide 10-[1-(Imino-phenyl-methyl)- 1s 382
piperidin-4-yl]-10H-phenoxazine-3- carboxylic acid diethylamide
N-{2-[10-(1-Benzyl-piperidin-4-yl)- 5h 400 3325
10H-phenoxazin-3-yl]-phenyl}- acetamide
3-[10-(1-Phenethyl-piperidin-4-yl)- 4b 401 10H-phenoxazin-3-yl]-4H-
[1,2,4]oxadiazol-5-one 10-Piperidin-4-yl-10H-phenoxazine- 11a 436
5816 1928 0.45 >10,000 3-carbonitrile
[10-(1-Benzyl-piperidin-4-yl)-10H- 13r 465 phenoxazin-3-yl]-(3-(S)-
Hydroxypyrrolidin-1-yl)-methanone 6e 475 3066
10-Piperidin-4-yl-3-pyridin-3-yl-10H- phenothiazine
10-(1-Phenethyl-piperidin-4-yl)-3- 9a 475
(1H-tetrazol-5-yl)-10H-phenoxazine
10-(1-Furan-3-ylmethyl-piperidin-4- 3g 500 964
yl)-3-pyridin-4-yl-10H-phenothiazine
10-Piperidin-4-yl-7-pyridin-4-yl-10H 4p 535 phenoxazin-4-ol
10-Piperidin-4-yl-3-pyridin-4-yl-10H- 2k 554 phenoxazine
N-{2-[10-(1-Thiophen-2-ylmethyl- 7g 571 4028
piperidin-4-yl)-10H-phenothiazin-3- yl]-phenyl}-acetamide
N-{2-[10-(1-Pyridin-2-ylmethyl- 5j 576
piperidin-4-yl)-10H-phenoxazin-3-yl]- phenyl}-acetamide
6-Methoxy-10-piperidin-4-yl-3- 5p 589 pyridin-4-yl-10H-phenoxazine
10-(1-Furan-3-ylmethyl-piperidin-4- 10r 655
yl)-10H-phenoxazine-3-carboxylic acid diethylamide
10-[1-(1H-Imidazol-2-ylmethyl)- 7a 655 2768
piperidin-4-yl]-3-(1H-tetrazol-5-yl)- 10H-phenoxazine
10-Piperidin-4-yl-10H-phenoxazine- 12a 682 1243 9247 0.81
>10,000 3-carboxylic acid amide
10-(1-Thiophen-2-ylmethyl-piperidin- 4m 784
4-yl)-10H-phenothiazine-3- carboxylic acid ethylamide
N,N-Diethyl-10-(1-methyl-piperidin- 3o 1017
4-yl)-10H-phenothiazine-3- carboxamidine
10-(1-Benzyl-piperidin-4-yl)-3- 4h 1089 >10000
pyridin-3-yl-10H-phenoxazine 10-(1-Methyl-piperidin-4-yl)-10H- 2q
1131 >10000 phenoxazine-3-carboxylic acid methyl ester
10-(1-Phenethyl-piperidin-4-yl)-10H- 11r 1177
phenoxazine-3-carboxylic acid diethylamide
10-(1-Methyl-piperidin-4-yl)-10H- 2m 1201
phenothiazine-3-carboxylic acid ethylamide
3-Pyridin-4-yl-10-(1-pyridin-2- 5k 1202
ylmethyl-piperidin-4-yl)-10H- phenoxazine
10-(1-Furan-3-ylmethyl-piperidin-4- 3k 1229
yl)-3-pyridin-4-yl-10H-phenoxazine
10-(1-Benzyl-piperidin-4-yl)-10H- 2r 1311 349
phenoxazine-3-carboxylic acid (3-(S)-Hydroxypyrrolidin-1-yl)-(10-
14r 1334 piperidin-4-yl-10H-phenoxazin-3-yl)- methanone
N-{2-[10-(1-Thiophen-2-ylmethyl- 4j 1393
piperidin-4-yl)-10H-phenoxazin-3-yl]- phenyl}-acetamide
3-Bromo-10-piperidin-4-yl-10H- 5e 1396 6936 phenothiazine
[10-(1-Methyl-piperidin-4-yl)-10H- 1m 1439
phenothiazin-3-yl]-pyrrolidin-1-yl- methanone
3-Bromo-10-(1-phenethyl-piperidin- 1g 1496 78
4-yl)-10H-phenothiazine 10-(1-Benzyl-piperidin-4-yl)-3- 2h 1576
3705 chloro-10H-phenoxazine 10-Piperidin-4-yl-10H- 1n 1576
phenothiazine-3-carbonitrile 10-(1-Thiophen-2-ylmethyl-piperidin-
12r 1652 4-yl)-10H-phenoxazine-3-carboxylic acid diethylamide
3-Chloro-6-methoxy-10-piperidin-4- 7p 1746 yl-10H-phenoxazine
10-(1-Phenethyl-piperidin-4-yl)-3- 2g 2057 43
pyridin-4-yl-10H-phenothiazine 10-(1-Benzyl-piperidin-4-yl)-3- 3h
2091 7108 pyridin-4-yl-10H-phenoxazine
10-(1-Phenethyl-piperidin-4-yl)-3- 6k 2125
pyridin-4-yl-10H-phenoxazine 10-Piperidin-4-yl-3-(1H-tetrazol-5- 4n
2239 yl)-10H-phenothiazine N-{2-[10-(1-Furan-3-ylmethyl- 3j 2275
piperidin-4-yl)-10H-phenoxazin-3-yl]- phenyl}-acetamide
10-(1-Methyl-piperidin-4-yl)-10H- 3q 2624 phenoxazine-3-carboxylic
acid (3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1- 5q 2628 >10000
methyl-piperidin-4-yl)-10H- phenoxazin-3-yl]-methanone
(3-Hydroxypyrrolidin-1-yl)-[10-(1- 3m 3150
methylpiperidin-4-yl)-10H- phenothiazin-3-yl]-methanone
(3-(S)-Hydroxypyrrolidin-1-yl)-[10-(1- 17r 3169
phenethyl-piperidin-4-yl)-10H- phenoxazin-3-yl]-methanone
(3-Hydroxypyrrolidin-1-yl)-[10-(1- 6m 3232
phenethyl-piperidin-4-yl)-10H- phenothiazin-3-yl]-methanone
3-Pyridin-4-yl-10-(1-thiophen-2- 4k 3617
ylmethyl-piperidin-4-yl)-10H- phenoxazine
10-(1-Methyl-piperidin-4-yl)-3-(1H- 2o 3956
tetrazol-5-yl)-10H-phenothiazine
3-Bromo-10-(1-methylpiperidin-4-yl)- 4e 4959 6932 10H-phenothiazine
3-Pyridin-3-yl-10-(1-thiophen-2- 7i 5132
ylmethyl-piperidin-4-yl)-10H- phenoxazine
N-{2-[10-(1-Phenethyl-piperidin-4- 6j 5374
yl)-10H-phenoxazin-3-yl]-phenyl}- acetamide
10-(1-Methyl-piperidin-4-yl)-10H- 1o 6205
phenothiazine-3-carbonitrile 10-(1-Benzylpiperidin-4-yl)-7- 4l 6279
diethylcarbamoyl-10H-phenoxazine- 4-carboxylic acid
10-(1-Phenethyl-piperidin-4-yl)-3- 8i >10000
pyridin-3-yl-10H-phenoxazine 3-Pyridin-3-yl-10-(1-pyridin-2- 6i
>10000 ylmethyl-piperidin-4-yl)-10H- phenoxazine
10-(1-Furan-3-ylmethyl-piperidin-4- 5i >10000
yl)-3-pyridin-3-yl-10H-phenoxazine 7-Chloro-10-piperidin-4-yl-10H-
8p >10000 phenoxazin-4-ol 10-(1-Benzoyl-piperidin-4-yl)-10H- 2s
>10000 phenoxazine-3-carboxylic acid diethylamide
* * * * *