U.S. patent application number 11/117759 was filed with the patent office on 2005-09-29 for 2,6-substituted chroman derivatives useful as beta-3 adrenoreceptor agonists.
This patent application is currently assigned to Bayer Pharmaceuticals Corporation. Invention is credited to Bullock, William H., Campbell, Ann-Marie, Dai, Miao, Dally, Robert, Dumas, Jacques, Hatoum-Mokdad, Holia N., Khire, Uday, Ladouceur, Gaetan H., Lee, Wendy, Liu, Qingjie, Lowe, Derek B., Magnuson, Steven R., O'Connor, Stephen J., Qi, Ning, Shen, Quanrong, Skelekhin, Tatiana E., Smith, Roger A., Wang, Ming.
Application Number | 20050215594 11/117759 |
Document ID | / |
Family ID | 26963345 |
Filed Date | 2005-09-29 |
United States Patent
Application |
20050215594 |
Kind Code |
A1 |
O'Connor, Stephen J. ; et
al. |
September 29, 2005 |
2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor
agonists
Abstract
This invention relates to novel 2,6-substituted chroman
derivatives which are useful in the treatment of beta-3
adrenoreceptor-mediated conditions.
Inventors: |
O'Connor, Stephen J.;
(Guilford, CT) ; Ladouceur, Gaetan H.; (Branford,
CT) ; Bullock, William H.; (Easton, CT) ;
Campbell, Ann-Marie; (Monroe, CT) ; Dai, Miao;
(Briarwood, NY) ; Dally, Robert; (Indianapolis,
IN) ; Dumas, Jacques; (Bethany, CT) ;
Hatoum-Mokdad, Holia N.; (Hamden, CT) ; Khire,
Uday; (Hamden, CT) ; Lee, Wendy; (Hamden,
CT) ; Liu, Qingjie; (Milford, CT) ; Lowe,
Derek B.; (Hamden, CT) ; Magnuson, Steven R.;
(Hamden, CT) ; Qi, Ning; (Hamden, CT) ;
Skelekhin, Tatiana E.; (Ridgefield, CT) ; Shen,
Quanrong; (Fishers, IN) ; Smith, Roger A.;
(Madison, CT) ; Wang, Ming; (Milford, CT) |
Correspondence
Address: |
JEFFREY M. GREENMAN
BAYER PHARMACEUTICALS CORPORATION
400 MORGAN LANE
WEST HAVEN
CT
06516
US
|
Assignee: |
Bayer Pharmaceuticals
Corporation
West Haven
CT
|
Family ID: |
26963345 |
Appl. No.: |
11/117759 |
Filed: |
April 28, 2005 |
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Application
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Patent Number |
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11117759 |
Apr 28, 2005 |
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10666903 |
Sep 17, 2003 |
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6919371 |
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10666903 |
Sep 17, 2003 |
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10131448 |
Apr 22, 2002 |
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6660752 |
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60285719 |
Apr 23, 2001 |
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60324518 |
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Current U.S.
Class: |
514/337 ;
546/283.1 |
Current CPC
Class: |
C07D 417/14 20130101;
C07D 413/12 20130101; C07D 405/12 20130101; C07D 405/14 20130101;
C07D 407/12 20130101; A61P 3/04 20180101; C07D 409/12 20130101;
A61P 9/10 20180101; A61P 13/02 20180101; A61P 13/00 20180101; A61P
3/08 20180101; A61P 5/48 20180101; A61P 9/06 20180101; C07D 311/58
20130101; A61P 3/10 20180101; A61P 1/04 20180101; A61P 13/04
20180101; A61P 9/00 20180101; A61P 13/12 20180101; A61P 3/06
20180101 |
Class at
Publication: |
514/337 ;
546/283.1 |
International
Class: |
A61K 031/4433; C07D
045/02 |
Claims
We claim:
1. A compound of Formula I 976wherein, R is independently hydroxy,
oxo, halo, cyano, nitro, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10
haloalkyl, CF.sub.3, NR.sup.1R.sup.1, SR.sup.1, OR.sup.1,
SO.sub.2R.sup.2, OCOR.sup.2, NR.sup.1COR.sup.2, COR.sup.2,
NR.sup.1SO.sub.2R.sup.2, phenyl, or a 5- or 6-membered heterocycle
with from 1 to 4 heteroatoms selected from O, S, and N; each cyclic
moiety being optionally substituted with hydroxy, R.sup.1, halo,
cyano, NR.sup.1R.sup.1, SR.sup.1, CF.sub.3, OR.sup.1,
C.sub.3-C.sub.8 cycloalkyl, NR.sup.1COR.sup.2, COR.sup.2,
SO.sub.2R.sup.2, OCOR.sup.2, NR.sup.1SO.sub.2R.sup.2
C.sub.1-C.sub.10 alkyl, or C.sub.1-C10 alkoxy; R.sup.1 is hydrogen,
(CH.sub.2).sub.d--O--(CH.sub.2).sub.dR.sup.5 where each d is
selected independently, or C.sub.1-C.sub.10 alkyl optionally
substituted with 1 to 4 substituents each independently selected
from hydroxy, halo, CO.sub.2C.sub.1-C.sub.4-alkyl, CO.sub.2H,
C.sub.1-C.sub.10 alkoxy, S(O).sub.bC.sub.1-C.sub.10 alkyl,
S(O).sub.b-phenyl optionally substituted with halo, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, SO.sub.2-C.sub.1-C.sub.4alkyl, or
CO.sub.2 C.sub.1-C.sub.4alkyl; or phenyl optionally substituted
with CO.sub.2C.sub.1-C.sub.4-alkyl, CO.sub.2H, halo, or
C.sub.1-C.sub.10 alkyl; or C.sub.3-C.sub.8 cycloalkyl, phenyl, or
naphthyl, each optionally substituted with 1 to 4 substituents each
independently selected from halo, nitro, oxo, C.sub.1-C.sub.10
alkyl, C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10 alkylthio,
CO.sub.2C.sub.1-C.sub.4-alkyl, and CO.sub.2H, and when two R.sup.1
groups are attached to N as NR.sup.1R.sup.1, these R.sup.1 groups
may form together with the nitrogen to which they are attached, a
heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0
to 1 O or S atoms; R.sup.2is R.sup.1, OR.sup.1, NR.sup.1R.sup.1,
NHS(O).sub.bphenyl optionally substituted with C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, halo or nitro; NHS(O).sub.bnaphthyl,
NHS(O).sub.bC.sub.1-C.sub.10alkyl optionally substituted with
fluoro up to the perfluoro level, or a 5- or 6-membered heterocycle
with one or more heteroatoms selected from O, S, and N, said
heterocyclic moiety being optionally substituted with R.sup.1;
R.sup.3 is hydrogen, C.sub.1-C.sub.10 alkyl, or COR.sup.2; R.sup.4
is hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl-phenyl,
or C.sub.1-C.sub.10 alkyl-pyridyl; R.sup.5 is hydrogen or COOH;
R.sup.6 is hydrogen, C.sub.1-C.sub.10 alkyl optionally substituted
with 1 to 4 substituents each independently selected from halo,
phenyl, or phenyl-COR.sup.2, or C.sub.1-C.sub.10
alkyl-S(O).sub.bC.sub.1-C.sub.10 alkyl optionally substituted with
COR.sup.2 or C.sub.3-C.sub.8 cycloalkyl; Ar is phenyl optionally
fused to a 5- or 6-membered heterocycle containing one or more
heteroatoms each independently selected from O, S, and N, said
bicyclic moiety being optionally fused to a phenyl, or a 5- or
6-membered heterocycle containing one or more heteroatoms each
independently selected from N, S, and O, optionally fused to
phenyl; Y is halo, NO.sub.2, R.sup.6 SR.sup.1,
S(O).sub.b-phenyl-CO.sub.2R.sup.1, 977where, when the two R.sup.4
groups attached to the same C are both alkyl, they optionally may
be joined so that, when taken together with the C to which they are
attached, they form a Spiro ring of 3, 5, or 6 C atoms, or where
the R.sup.4 attached to N and one R.sup.4 attached to the adjacent
C are both alkyl, they optionally may be joined so that, taken
together with the atoms to which they are attached, they form a 5-
or 6-membered heterocyclic ring; with the proviso that when e is 1,
at least one R.sup.4 group must be C.sub.1-C.sub.10 alkyl-phenyl or
C.sub.1-C.sub.10 alkyl-pyridyl, or two R.sup.4 groups must form one
of said spiro or heterocyclic ring moieties; a phenyl optionally
fused to one or two phenyl rings, or to a 5- or 6-membered
heterocycle containing one or more heteroatoms each independently
selected from N, S, and O, or a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
N, S and O, optionally fused to a phenyl ring, each cyclic moiety
being optionally substituted with one or more substituents
independently selected from COR.sup.2, CONR.sup.1S(O).sub.2R.sup.9,
COCH.sub.2SO.sub.2-thiazolyl optionally substituted with alkyl or
amino, halo, NO.sub.2, OR.sup.1, R.sup.1, SR.sup.1,
O--C.sub.1-C.sub.6-alkyl substituted by C.sub.3-C.sub.6-cycloalkyl,
O-phenyl optionally substituted by SO.sub.2CH.sub.3,
SO.sub.2NH.sub.2, SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
NR.sup.1COC.sub.1-C.sub.6alkyl, 978C.sub.1-C.sub.10COR.sup.2,
phenyl optionally substituted with halo, C.sub.1-C.sub.4 alkyl, or
C.sub.1-C.sub.4 alkoxy, tetrazolo; R.sup.7 is phenyl or heteroaryl
containing 3-6 C and 1-3 O, N, or S atoms, each optionally
substituted by C.sub.1-C.sub.4 alkyl, CN, NO.sub.2,
CO-C.sub.1-C.sub.4alkyl, C1-C.sub.4 alkoxy, or C.sub.1-C.sub.4
haloalkyl, CO--R.sup.8, 979R.sup.8 is C.sub.1-C.sub.6 alkyl
optionally substituted with C.sub.1-C.sub.4 alkoxy,
N(CH.sub.3).sub.2,or one or two CF.sub.3,
C.sub.3-C.sub.6-cycloalkyl, phenyl optionally substituted with
C.sub.1-C.sub.4alkoxy, halo, or C.sub.1-C.sub.4alkyl, NH-phenyl
optionally substituted with C.sub.1-C.sub.4 alkyl, halo,
C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 haloalkoxy,
NH-cyclohexyl; R.sup.9 is C.sub.3-C.sub.6cycloalkyl, thienyl
optionally substituted with C.sub.1-C.sub.4 alkyl or isoxazolyl,
pyridyl optionally substituted with
--SO.sub.2--C.sub.1-C.sub.4alkyl, pyrazolyl optionally substituted
with halo or C.sub.1-C.sub.4 alkyl, isoxazolyl optionally
substituted with C.sub.1-C.sub.4 alkyl, or 980a is 0, 1, 2, 3, 4,
or 5; b is 0, 1, or 2; d is 1, 2, or 3; e is 1 or 2; and
pharmaceutically acceptable salts and esters thereof.
2. The compound of claim 1 wherein Y is halo, R.sup.6, SR.sup.1,
S(O).sub.b-phenyl-CO.sub.2R.sup.1, phenyl optionally fused to one
or two phenyl rings, or to a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
N, S, and O, or a 5- or 6-membered heterocycle containing one or
more heteroatoms each independently selected from N, S and O,
optionally fused to a phenyl ring, each cyclic moiety being
optionally substituted with one or more substituents independently
selected from COR.sup.2, halo, NO.sub.2, OR.sup.1, R.sup.1,
SR.sup.1, SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
NR.sup.1COC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.10COR.sup.2, phenyl,
tetrazolo; and pharmaceutically acceptable salts and esters
thereof.
3. The compound of claim 1 wherein Y is phenyl optionally fused to
one or two phenyl rings, or to a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
N, S, and O, or a 5- or 6- membered heterocycle containing one or
more heteroatoms each independently selected from N, S and O,
optionally fused to a phenyl ring, each cyclic moiety being
optionally substituted with one or more substituents independently
selected from COR.sup.2, halo, NO.sub.2, OR.sup.1, R.sup.1,
SR.sup.1, SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
NR.sup.1COC.sub.1-C.sub.6alkyl, C.sub.1-C.sub.10COR.sup.2, phenyl,
tetrazolo; and d is 1or 2; and pharmaceutically acceptable salts
and esters thereof.
4. The compound of claim 1 wherein Y is phenyl optionally fused to
one or two phenyl rings, or to a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
N, S, and O, or a 5- or 6- membered heterocycle containing one or
more heteroatoms each independently selected from N, S and O,
optionally fused to a phenyl ring, each cyclic moiety being
optionally substituted with one or more substituents independently
selected from COR.sup.2, halo, NO.sub.2, OR.sup.1, R.sup.1,
SR.sup.1, SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
C.sub.1-C.sub.10COR.sup.2, phenyl, tetrazolo; Ar is phenyl
optionally fused to a 5- or 6-membered heterocycle containing one
or more heteroatoms each independently selected from O, S, and N,
said bicyclic moiety being optionally fused to a phenyl, or a 5- or
6-membered heterocycle containing one or more heteroatoms each
independently selected from N, S, and O, optionally fused to
phenyl; and d is 1 or 2; and pharmaceutically acceptable salts and
esters thereof.
5. The compound of claim 1 wherein Y is phenyl optionally fused to
one or two phenyl rings, or to a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
N, S, and O, or a 5- or 6- membered-heterocycle containing one or
more heteroatoms each independently selected from N, S and O,
optionally fused to a phenyl ring, each cyclic moiety being
optionally substituted with one or more substituents independently
selected from COR.sup.2, halo, OR.sup.1, R.sup.1, NR.sup.1R.sup.1,
Ar is phenyl or a 5- or 6-membered heterocycle containing one or
more N atoms; a is 0, 1, 2, or 3; and d is 1; and pharmaceutically
acceptable salts and esters thereof.
6. A compound selected from the group consisting of:
2-[4-(ethoxycarbonyl)phenoxy]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)-
ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-isobutylbenzoic acid;
N-{3-[(2R)-2-({[(2R)-2-hydroxy--
2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-2--
methylbenzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl-
]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic
acid;
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]benzoyl}-4-methoxybenzenesulfonamide;
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]benzoyl}-1-propanesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-N-(4-methoxybenzoyl)benzenesulfonamide;
N-(2-cyano-4-nitrophenyl)-3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
2-(4-chlorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amin-
o}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
N-(4,6-dimethoxy-2-pyrimidinyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridiny-
l)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)ben-
zenesulfonamide;
2-(4-fluorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyri-
dinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-N-(3-methoxybenzoyl)benzenesulfonamide;
4-fluoro-N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl-
)-3,4-dihydro-2H-chromen-6-yl]benzoyl}benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-(4-methylphenoxy)benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid;
3-chloro-4-[(2R)-2-({[(2-
R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-y-
l]benzoic acid;
N-(4-fluorobenzoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyrid-
inyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-3-methoxybenzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-
-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-phenoxybenzo-
ic acid;
N-(4-cyanophenyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesu-
lfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)--
3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)-2-(trifl-
uoromethoxy)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl-
)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3,3,3-trifluoropropan-
oyl)benzenesulfonamide;
2-hydroxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridin-
yl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
3-((1R)-2-{[((2R)-6-{4-[({[(4-fluorophenyl)amino]carbonyl}amino)sulfonyl]-
phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide;
N-benzoyl-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)--
3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydrox-
y-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-propox-
ybenzoic acid;
N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-
methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)-4-methoxybenzen-
esulfonamide;
3-((1R)-1-hydroxy-2-{[((2R)-6-{4-[({[(4-methylphenyl)amino]c-
arbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}et-
hyl)pyridine;
3-((1R)-2-{[((2R)-6-{4-[({[(4-chloro-2-methylphenyl)amino]ca-
rbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1--
hydroxyethyl)pyridine;
N-(ethoxyacetyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-p-
yridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamid-
e;
N-(3,3-dimethylbutanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)eth-
yl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-[4-(methylsulfonyl)phenoxy]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-3-methylbenzoic acid;
4-{2-[(2R)-2-({[(2R)-2-hydroxy-2--
(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic
acid;
N-(2,2-dimethylpropanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridiny-
l)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;
3-[(1R)-2-({[(2R)-6-(4-{[(anilinocarbonyl)amino]sulfonyl}phenyl)-3,4-dihy-
dro-2H-chromen-2-yl]methyl}amino)-1-hydroxyethyl]pyridine;
2-ethoxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3--
pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6--
methyl-2-pyrimidinyl)benzenesulfonamide;
3-{(1R)-2-[({(2R)-6-[4-({[(cycloh-
exylamino)carbonyl]amino}sulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}meth-
yl)amino]-1-hydroxyethyl}pyridine;
N-(cyclopropylcarbonyl)-4-[(2R)-2-({[(2-
R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-y-
l]benzenesulfonamide;
2-chloro-5-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-p-
yridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic
acid;
4-[(4-[R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihy-
dro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridin-
yl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methylbenzoic
acid;
2-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3--
pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-propoxybenzoi-
c acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-
-dihydro-2H-chromen-6-yl]-2-isopropoxybenzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-(4-methoxyphenoxy)benzoic acid;
3-(cyclopropylmethoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]a-
mino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]benzenesulfonamide;
5-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyr-
idinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4'-methyl-1,1'-bip-
henyl-2-carboxylic acid;
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)eth-
yl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonami-
de;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]-N-(3-pyridinyl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-methoxybenzoic acid;
4-chloro-N-{6-[(2R)-2-({[(2R)-2--
hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3--
pyridinyl}benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)e-
thyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-isobutoxybenzoic
acid;
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]-3-pyridinyl}methanesulfonamide;
3-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]ethyl}benzoic acid;
3-[(1E)-1-hexenyl]-4-[(2R)-2-({[(-
2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6--
yl]benzoic acid;
3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}me-
thyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2-(2-methoxyethoxy)benzoic acid;
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydr-
o-2H-chromen-6-yl]-2,6-dimethylbenzoic acid;
4-[(2R)-2-({[(2R)-2-(6-amino--
3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benz-
oic acid;
3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}m-
ethyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;
(1R)-1-(6-amino-3-pyridin-
yl)-2-[({(2R)-6-[4-(1H-tetraazol-5-yl)phenyl]-3,4-dihydro-2H-chromen-2-yl}-
methyl)amino]ethanol;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-
amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-phenyl-1,2I5,3I5,4-thi-
atriazole-2-carboxylic acid;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl-
)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-furoic
acid;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid;
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]phenyl}-3-thiophenecarboxylic acid;
4-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dih-
ydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid;
6-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,-
4-dihydro-2H-chromen-6-yl]nicotinic acid;
5-[(2R)-2-({[(2R)-2-(6-amino-3-p-
yridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotin-
ic acid;
2-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}me-
thyl)-3,4-dihydro-2H-chromen-6-yl]-4-pyridinecarboxylic acid;
1-({[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)--
3,4-dihydro-2H-chromen-6-yl]carbonyl}amino)cyclopropanecarboxylic
acid; and
4-[(2R)-2-({[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}methyl)-3,4-
-dihydro-2H-chromen-6-yl]benzoic acid (Example 344).
7. A method of treating a beta-3 adrenergic receptor-mediated
condition comprising the step of administering to a patient in need
thereof a pharmaceutically effective amount of a compound of claim
1.
8. A method of treating obesity comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of a compound of claim 1.
9. A method of treating diabetes comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of a compound of claim 1.
10. A method of treating a patient with impaired fasting glucose or
impaired glucose tolerance comprising the step of administering to
said patient in need thereof a pharmaceutically effective amount of
a compound of claim 1.
11. A method of treating gastrointestinal disorders comprising the
step of administering to a patient in need thereof a
pharmaceutically effective amount of a compound of claim 1.
12. A method of treating hypertriglyceridemia, hypercholesteolemia,
atherosclerotic disorders, or cardiovascular disorders comprising
the step of administering to a patient in need thereof a
pharmaceutically effective amount of a compound of claim 1.
13. A method for lowering high-density lipoprotein levels
comprising the step of administering to a patient in need thereof a
pharmaceutically effective amount of a compound of claim 1.
14. A method for treating urinary disorders comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of a compound of claim 1.
15. The method of claim 14, wherein said urinary disorders is
selected from the group consisting of pollakiuria and
incontinence.
16. A method of treating a beta-3 adrenergic receptor-mediated
condition comprising the step of administering to a patient in need
thereof a pharmaceutically effective amount of a compound of claim
6.
17. A method of treating obesity comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of a compound of claim 6.
18. A method of treating diabetes comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of a compound of claim 6.
19. A method of treating a patient with impaired fasting glucose or
impaired glucose tolerance comprising the step of administering to
said patient in need thereof a pharmaceutically effective amount of
a compound of claim 6.
20. A method of treating gastrointestinal disorders comprising the
step of administering to a patient in need thereof a
pharmaceutically effective amount of a compound of claim 6.
21. A method of treating hypertriglyceridemia, hypercholesteolemia,
atherosclerotic disorders, or cardiovascular disorders comprising
the step of administering to a patient in need thereof a
pharmaceutically effective amount of a compound of claim 6.
22. A method for lowering high-density lipoprotein levels
comprising the step of administering to a patient in need thereof a
pharmaceutically effective amount of a compound of claim 6.
23. A method for treating urinary disorders comprising the step of
administering to a patient in need thereof a pharmaceutically
effective amount of a compound of claim 6.
24. The method of claim 23, wherein said urinary disorders is
selected from the group consisting of pollakiuria and
incontinence.
25. A pharmaceutical composition comprising an effective amount of
a compound of claim 1 or a pharmaceutically acceptable salt and
esters thereof in combination with a pharmaceutically acceptable
carrier.
26. A pharmaceutical composition for the treatment of obesity,
diabetes, gastrointestinal disorders, hypertriglyceridaemia,
hypercholesterolaemia, atherosclerosis, cardiovascular diseases, or
urinary disorders comprising an effective amount of a compound of
claim 1 or a pharmaceutically acceptable salt and ester thereof in
combination with a pharmaceutically acceptable carrier.
27. A composition comprising an effective amount of a compound of
claim 1 or a salt and esters thereof in combination with an inert
carrier.
28. A pharmaceutical composition comprising an effective amount of
a compound of claim 6 or a pharmaceutically acceptable salt and
esters thereof in combination with a pharmaceutically acceptable
carrier.
29. A pharmaceutical composition for the treatment of obesity,
diabetes, gastrointestinal disorders, hypertriglyceridaemia,
hypercholesterolaemia, atherosclerosis, cardiovascular diseases, or
urinary disorders comprising an effective amount of a compound of
claim 6 or a pharmaceutically acceptable salt and ester thereof in
combination with a pharmaceutically acceptable carrier.
30. A composition comprising an effective amount of a compound of
claim 6 or a salt and esters thereof in combination with an inert
carrier.
Description
[0001] This application claims benefit of U.S. Provisional
Application Ser. No. 60/285,719, filed Apr. 23, 2001, and U.S.
Provisional Application Ser. No. 60/324,518, filed on Sep. 26,
2001, the contents of which are incorporated herein by reference in
their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to novel chroman compounds,
pharmaceutical compositions containing such compounds, and methods
of treating beta-3 adrenoreceptor-mediated conditions with such
compositions.
BACKGROUND OF THE INVENTION
[0003] Adrenoreceptors, or adrenergic receptors, are sites on
effector organs that are innervated by postganglionic adrenergic
fibers of the sympathetic nervous system, and are classified as
either alpha-adrenergic or beta-adrenergic receptors.
Alpha-adrenergic receptors respond to norepinephrine and to such
blocking agents as phenoxybenzamine and phentolamine, whereas
beta-adrenergic receptors respond to epinephrine and to such
blocking agents as propranolol.
[0004] Beta-adrenergic receptors are sub-classified as beta-1,
beta-2, and beta-3 adrenoreceptors. Generally, beta-1 stimulation
causes cardiostimulation, whereas beta-2 stimulation causes
bronchodilation and vasodilation.
[0005] Beta-3 receptors are found on the cell surface of both white
and brown adipocytes where their stimulation promotes both
lipolysis and energy expenditure. Agonists of beta-3
adrenoreceptors are known to be useful in the treatment of
hyperglycemia (diabetes) and obesity in mammals, as well as in the
treatment of gastrointestinal disorders and neurogenetic
inflammation (U.S. Pat. No. 5,561,142). Additionally, they are
known to lower triglyceride and cholesterol levels and to raise
high-density lipoprotein levels in mammals (U.S. Pat. No.
5,451,677). Accordingly, they are useful in the treatment of
conditions such as hypertriglyceridemia, hypercholesterolemia, and
in lowering high-density lipoprotein levels. They also may be
useful in treating patients with Syndrome X, impaired fasting
glucose, and/or impaired glucose tolerance, as well as in the
treatment of atherosclerotic and cardiovascular diseases and
related conditions.
[0006] Additionally, it is also believed that the compounds of this
invention are effective in the treatment of ocular hypertension and
glaucoma, and in the treatment of urinary disorders including
pollakiuria and incontinence, as well as in the treatment of
prostate disease and as topical anti-inflammatory agents.
[0007] It has now been found that certain novel chroman derivatives
are effective as beta-3 agonists and are useful in the treatment of
beta-3 adrenoreceptor-mediated conditions.
DESCRIPTION OF THE INVENTION
[0008] 1
[0009] wherein,
[0010] R is independently
[0011] hydroxy,
[0012] oxo,
[0013] halo,
[0014] cyano,
[0015] nitro,
[0016] C.sub.1-C.sub.10 alkyl,
[0017] C.sub.1-C.sub.10 haloalkyl,
[0018] CF.sub.3,
[0019] NR.sup.1R.sup.1,
[0020] SR.sup.1,
[0021] OR.sup.1,
[0022] SO.sub.2R.sup.2,
[0023] OCOR.sup.2,
[0024] NR.sup.1COR.sup.2,
[0025] COR.sup.2,
[0026] NR.sup.1SO.sub.2R.sup.2,
[0027] phenyl, or
[0028] a 5- or 6-membered heterocycle with from 1 to 4 heteroatoms
selected from O, S, and N;
[0029] each cyclic moiety being optionally substituted with
[0030] hydroxy,
[0031] R.sup.1,
[0032] halo,
[0033] cyano,
[0034] NR.sup.1R.sup.1,
[0035] SR.sup.1,
[0036] CF.sub.3,
[0037] OR.sup.1,
[0038] C.sub.3-C.sub.8 cycloalkyl,
[0039] NR.sup.1COR.sup.2,
[0040] COR.sup.2,
[0041] SO.sub.2R.sup.2,
[0042] OCOR.sup.2,
[0043] NR.sup.1SO.sub.2R.sup.2,
[0044] C.sub.1-C.sub.10 alkyl, or
[0045] C.sub.1-C.sub.10 alkoxy;
[0046] R.sup.1 is
[0047] hydrogen,
[0048] (CH.sub.2).sub.d--O--(CH.sub.2).sub.dR.sup.5 where each d is
selected independently, or
[0049] C.sub.1-C.sub.10 alkyl optionally substituted with 1 to 4
substituents each independently selected from
[0050] hydroxy,
[0051] halo,
[0052] CO.sub.2C.sub.1-C.sub.4-alkyl,
[0053] CO.sub.2H,
[0054] C.sub.1-C.sub.10 alkoxy,
[0055] S(O).sub.bC.sub.1-C.sub.10 alkyl,
[0056] S(O).sub.b-phenyl optionally substituted with halo,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4 alkoxy,
SO.sub.2--C.sub.1-C.sub.4al- kyl, or CO.sub.2 C.sub.1-C.sub.4alkyl;
or
[0057] phenyl optionally substituted with
CO.sub.2C.sub.1-C.sub.4-alkyl, CO.sub.2H, halo, or C.sub.1-C.sub.10
alkyl;
[0058] or
[0059] C.sub.3-C.sub.8 cycloalkyl, phenyl, or naphthyl, each
optionally substituted with 1 to 4 substituents each independently
selected from halo, nitro, oxo, C.sub.1-C.sub.10 alkyl,
C.sub.1-C.sub.10alkoxy, C.sub.1-C.sub.10 alkylthio,
CO.sub.2C.sub.1-C.sub.4-alkyl, and CO.sub.2H, and
[0060] when two R.sup.1 groups are attached to N as
NR.sup.1R.sup.1, these R.sup.1 groups may form together with the
nitrogen to which they are attached, a heterocyclic ring containing
4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;
[0061] R.sup.2is
[0062] R.sup.1,
[0063] OR.sup.1,
[0064] NR.sup.1R.sup.1,
[0065] NHS(O).sub.bphenyl optionally substituted with
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, halo or nitro;
[0066] NHS(O).sub.bnaphthyl,
[0067] NHS(O).sub.bC.sub.1-C.sub.10alkyl optionally substituted
with fluoro up to the perfluoro level, or
[0068] a 5- or 6-membered heterocycle with one or more heteroatoms
selected from O, S, and N, said heterocyclic moiety being
optionally substituted with R.sup.1;
[0069] R.sup.3 is hydrogen, C.sub.1-C.sub.10 alkyl, or
COR.sup.2;
[0070] R.sup.4 is hydrogen, C.sub.1-C.sub.10 alkyl,
C.sub.1-C.sub.10 alkyl-phenyl, or C.sub.1-C.sub.10
alkyl-pyridyl;
[0071] R.sup.5 is hydrogen or COOH;
[0072] R.sup.6 is
[0073] hydrogen,
[0074] C.sub.1-C.sub.10 alkyl optionally substituted with 1 to 4
substituents each independently selected from halo, phenyl, or
phenyl-COR.sup.2, or
[0075] C.sub.1-C.sub.10 alkyl-S(O).sub.bC.sub.1-C.sub.10 alkyl
optionally substituted with COR.sup.2 or C.sub.3-C.sub.8
cycloalkyl;
[0076] Ar is
[0077] phenyl optionally fused to a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
O, S, and N, said bicyclic moiety being optionally fused to a
phenyl, or
[0078] a 5- or 6-membered heterocycle containing one or more
heteroatoms each independently selected from N, S, and O,
optionally fused to phenyl;
[0079] Y is
[0080] halo,
[0081] NO.sub.2,
[0082] R.sup.6,
[0083] SR.sup.1,
[0084] S(O).sub.b-phenyl-CO.sub.2R.sup.1, 2
[0085] where, when the two R.sup.4 groups attached to the same C
are both alkyl, they optionally may be joined so that, when taken
together with the C to which they are attached, they form a spiro
ring of 3, 5, or 6 C atoms, or where the R.sup.4 attached to N and
one R.sup.4 attached to the adjacent C are both alkyl, they
optionally may be joined so that, taken together with the atoms to
which they are attached, they form a 5- or 6-membered heterocyclic
ring;
[0086] with the proviso that when e is 1, at least one R.sup.4
group must be C.sub.1-C.sub.10 alkyl-phenyl or C.sub.1-C.sub.10
alkyl-pyridyl, or two R.sup.4 groups must form one of said spiro or
heterocyclic ring moieties,
[0087] phenyl optionally fused to one or two phenyl rings, or to a
5- or 6-membered heterocycle containing one or more heteroatoms
each independently selected from N, S, and O, or
[0088] a 5- or 6-membered heterocycle containing one or more
heteroatoms each independently selected from N, S and O, optionally
fused to a phenyl ring,
[0089] each cyclic moiety being optionally substituted with one or
more substituents independently selected from
[0090] COR.sup.2,
[0091] CONR.sup.1S(O).sub.2R.sup.9,
[0092] COCH.sub.2SO.sub.2-thiazolyl optionally substituted with
alkyl or amino,
[0093] halo,
[0094] NO.sub.2,
[0095] OR.sup.1,
[0096] R.sup.1,
[0097] SR.sup.1,
[0098] O--C.sub.1-C.sub.6-alkyl substituted by
C.sub.3-C.sub.6-cycloalkyl,
[0099] O-phenyl optionally substituted by SO.sub.2CH.sub.3,
[0100] SO.sub.2NH.sub.2,
[0101] SO.sub.2NR.sup.1R.sup.7,
[0102] NR.sup.1R.sup.1,
[0103] NR.sup.1COC.sub.1-C.sub.6alkyl, 3
[0104] C.sub.1-C.sub.10COR.sup.2,
[0105] phenyl optionally substituted with halo, C.sub.1-C.sub.4
alkyl, or C.sub.1-C.sub.4 alkoxy,
[0106] tetrazolo;
[0107] R.sup.7 is
[0108] phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S
atoms, each optionally substituted by C.sub.1-C.sub.4alkyl, CN,
NO.sub.2, CO--C.sub.1-C.sub.4alkyl, C1-C.sub.4alkoxy, or
C.sub.1-C.sub.4 haloalkyl,
[0109] CO--R.sup.8, 4
[0110] R.sup.8 is
[0111] C.sub.1-C.sub.6alkyl optionally substituted with
C.sub.1-C.sub.4 alkoxy, N(CH.sub.3).sub.2,or one or two
CF.sub.3,
[0112] C.sub.3-C.sub.6-cycloalkyl,
[0113] phenyl optionally substituted with C.sub.1-C.sub.4 alkoxy,
halo, or C.sub.1-C.sub.4 alkyl,
[0114] NH-phenyl optionally substituted with C.sub.1-C.sub.4alkyl,
halo, C.sub.1-C.sub.4alkoxy, or C.sub.1-C.sub.4 haloalkoxy,
[0115] NH-cyclohexyl;
[0116] R.sup.9 is
[0117] C.sub.3-C.sub.6 cycloalkyl,
[0118] thienyl optionally substituted with C.sub.1-C.sub.4 alkyl or
isoxazolyl,
[0119] pyridyl optionally substituted with
--SO.sub.2--C.sub.1-C.sub.4alky- l,
[0120] pyrazolyl optionally substituted with halo or
C.sub.1-C.sub.4alkyl,
[0121] isoxazolyl optionally substituted with C.sub.1-C.sub.4
alkyl, or 5
[0122] a is 0, 1, 2, 3, 4, or 5;
[0123] b is 0, 1, or 2;
[0124] d is 1, 2, or 3;
[0125] e is 1 or 2;
[0126] and pharmaceutically acceptable salts and esters
thereof.
[0127] The terms identified above have the following meaning
throughout:
[0128] C.sub.1-C.sub.10 alkyl means straight or branched chain
alkyl groups having from one to about ten carbon atoms, which may
be saturated, unsaturated, or partially saturated. Such groups
include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, as well as vinyl, allyl, propynyl, butenyl,
butadienyl, isopropenyl, methyleneyl, ethylenyl, propenyl, ethynyl,
and the like.
[0129] C.sub.1-C.sub.10 haloalkyl means straight or branched chain
alkyl groups having from about one to about ten carbon atoms where
any C--C bond may be saturated or unsaturated, the alkyl groups
being substituted at any available carbon atom with one or more
halogen atoms, and includes such groups as trifluoromethyl,
trichloromethyl, pentafluoroethyl, fluoromethyl, 6-chlorohexyl, and
the like.
[0130] The term C.sub.1-C.sub.10 alkoxy means straight or branched
chain alkoxy groups having from one to about ten carbon atoms where
any C--C bond may be saturated or unsaturated, and includes such
groups as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec-butoxy, tert-butoxy, and the like.
[0131] The term C.sub.1-C.sub.10 alkylthio means straight or
branched chain alkylthio groups having from one to about ten carbon
atoms where any C--C bond may be saturated or unsaturated, and
includes such groups as methylthio, ethylthio, n-propylthio,
isopropylthio, n-butylthio, isobutylthio, sec-butylthio,
tert-butylthio, and the like.
[0132] C.sub.3-C.sub.8 cycloalkyl means saturated mono cyclic alkyl
groups of from 3 to about 8 carbon atoms, and includes such groups
as cyclopropyl, cyclopentyl, cyclohexyl, and the like.
[0133] Halo includes fluoro, chloro, bromo, and iodo, unless
specifically stated otherwise.
[0134] R, R.sup.2, Ar, and Y each include any 5- or 6-membered
saturated or unsaturated heterocyclic group having any combination
of one or more N, S, or O atoms with the point of attachment being
at any available position on the heterocyclic ring. Where there is
more than one heteroatom in a single cyclic group, each heteroatom
shall be chosen independently of any other heteroatom, in each
occurrence, with the proviso that any single heterocyclic ring may
not contain more than two oxygen or sulfur atoms. These moieties
include such 5-membered heterocylic groups as furyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,
isothiazolyl, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl,
pyrrolinyl, dihydrothienyl, tetrahydrothienyl, dioxolyl,
dithiolanyl, oxazolinyl, oxazolidinyl, isoxazolinyl,
isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl,
isothiazolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl,
pyrazolidinyl, triazolyl, triazolinyl, triazolidinyl, oxadiazolyl,
thiadiazolyl, furazanyl, tetrazolyl, and the like. It also includes
such 6-membered heterocyclic rings such as pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, pyranyl, dihydropyranyl, thiopyranyl,
triazinyl, dioxanyl, piperidinyl, piperazinyl, pyrazinyl,
morpholinyl, and the like
[0135] Ar and Y also each include phenyl fused to any 5- or
6-membered heterocyclic ring described above to form a bicyclic
moiety, which may be saturated or unsaturated and may have any
combination of one or more N, S, or O atoms with the point of
attachment being any at available position on the phenyl ring.
These include such phenyl fused 5-membered heterocyclic groups as
benzofuryl, dihydrobenzofuryl, benzothienyl, dihydrobenzothienyl,
indolyl, indazolyl, indolinyl, indazolinyl, benzoxazolyl,
benzoxazolinyl, benzothiazolyl, benzothiazolinyl, benzimidazolyl,
benzimidazolinyl, benzisoxazolyl, benzisoxazolinyl,
benzothiadiazolinyl, benzisothiazolyl, benzisothiazolinyl,
benzotriazolyl, benzoxadiazolyl, benzoxadiazolinyl,
benzothiadiazolyl, benzopyrazolinyl, and the like. It also includes
such phenyl fused 6-membered heterocyclic groups as quinolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl,
phthalazinyl, dihydrobenzopyranyl, benzothiopyranyl,
dihydrobenzothiopyranyl, benzoxazinyl, benzodioxanyl,
benzodioxenyl, and the like.
[0136] Ar also includes phenyl fused to any 5- or 6-membered
heterocyclic ring to form a bicyclic moiety as described above,
which is further fused on the heterocyclic ring to a second phenyl
ring, forming a tricyclic system, with the point of attachment to
the core structure of the compound of Formula I being at any
available position of the first phenyl ring. These include such
groups as carbazolyl, carbazolinyl, acridinyl, xanthenyl,
phenoxathiinyl, phenoxazinyl, phenanthridinyl, dibenzofuryl,
dibenzopyranyl, dibenzodioxanoyl, phenazinyl, thianthrenyl, and the
like.
[0137] Ar also includes any 5- or 6-membered saturated or
unsaturated heterocyclic ring having any combination of one or more
N, S, or O atoms as described above, which is further fused to a
phenyl ring, with the point of attachment to the core molecule of
Formula I being at any available position on the heterocyclic ring.
These include such phenyl-fused with 5-membered hetero-bicyclic
moieties as benzofuryl, dihydrobenzofuryl, benzothienyl,
dihydrobenzothienyl, indolyl, indazolyl, indolizinyl, indolinyl,
indazolinyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl,
benzothiazolinyl, benzimidazolyl, benzimidazolinyl, benzisoxazolyl,
benzisoxazolinyl, benzisothiazolyl, benzoisothiazolinyl,
benzopyrazolinyl and the like. It also includes such phenyl-fused
with 6-membered hetero-bicyclic groups as quinolyl, isoquinolyl,
quinazolinyl, quinoxalinyl, cinnolinyl, chromenyl, phthalazinyl,
dihydrobenzopyranyl, benzothiopyranyl, dihydrobenzothiopyranyl,
benzoxazinyl, benzodioxanyl, benzodioxenyl, and the like.
[0138] C.sub.1-C.sub.10-alkyl-phenyl means saturated straight or
branched chain alkyl groups having from one to about ten carbon
atoms where the phenyl moiety is attached at any available position
on the alkyl group. Examples of these moieties include benzyl,
2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl,
1-methyl-2-phenylethyl, 5-phenylpentyl, 4-phenylhexyl, and the
like.
[0139] C.sub.1-C.sub.10-alkyl-pyridyl means straight or branched
chain saturated alkyl groups having from one to about ten carbon
atoms where the pyridyl moiety is attached at any available
position on the alkyl group. The pyridyl group may be attached to
the alkyl group from any available position on the pyridine ring.
Examples of these include pyridyl, 2-(2-pyridyl)ethyl,
3-(4-pyridyl)-propyl, 2-(3-pyridyl)-propyl,
1-methyl-2-(3-pyridyl)-ethyl, 5-(3-pyridyl)-pentyl,
4-(4-pyridyl)-hexyl, and the like.
[0140] S(O).sub.b-phenyl-CO.sub.2R.sup.1 means a phenylthio, a
phenylsulfinyl, or a phenylsulfonyl group, where the
CO.sub.2R.sup.1 moiety is attached at any available position on the
phenyl ring.
[0141] When any moiety is described as being substituted, it can
have one or more of the indicated substituents that can be located
at any available position on the moiety. When there are two or more
substituents on any moiety, each term shall be defined
independently of any other in each occurrence. For example,
NR.sup.1R.sup.1 may represent NH.sub.2, NHCH.sub.3,
N(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3, and the like.
[0142] Examples of the compound of Formula I, which are
illustrative of the present invention but not limiting in any way,
are listed in Table 1.
1TABLE 1 (I) 6 Entry No. R a Ar R.sup.3 d Y 1 7 1 8 H 1 9 2 10 1 11
H 2 12 3 13 1 14 H 3 15 4 6-NH.sub.2 1 16 H 1 l 5 6-NH.sub.2 1 17 H
1 Br 6 6-NH.sub.2 1 18 H 1 --NO.sub.2 7 6-NH.sub.2 1 19 H 1
--.ident.-t-Bu 8 6-NH.sub.2 1 20 H 1 --.ident.-Ph 9 6-NH.sub.2 1 21
H 1 --S--CH.sub.2--CO.sub.3Et 10 6-NH.sub.2 1 22 H 2
--S--CH.sub.2--CO.sub.3H 11 6-NH.sub.2 1 23 H 1 24 12 6-NH.sub.2 1
25 H 2 26 13 6-NH.sub.2 1 27 H 1 28 14 6-NH.sub.2 1 29 H 2 30 15
6-NH.sub.2 1 31 H 3 32 16 -- 0 Ph H 1 33 17 -- 0 Ph H 1 34 18 -- 0
35 H 1 36 19 -- 0 37 H 2 38 20 6-NH.sub.2 1 39 H 1 40 21 -- 0 41 H
1 42 22 -- 0 43 H 1 44 23 -- 0 45 H 2 46 24 -- 0 47 H 1 48 25 -- 0
49 H 1 50 26 -- 0 Ph H 1 51 27 -- 0 52 H 3 53 28 -- 0 54 H 1 55 29
-- 0 56 H 1 57 30 -- 0 58 H 1 59 31 -- 0 60 H 1 61 32 -- 0 62 H 1
63 33 -- 0 64 H 1 65 34 -- 0 66 H 1 67 35 -- 0 68 H 1 69 36 -- 0 70
H 1 71 37 -- 0 72 H 1 73 38 -- 0 74 H 1 75 39 -- 0 76 H 1 77 40 --
0 78 H 1 79 41 -- 0 80 H 1 81 42 -- 0 82 H 1 83 43 -- 0 84 H 1 85
44 -- 0 86 H 1 87 45 -- 0 88 H 1 89 46 -- 0 90 H 1 91 47 -- 0 92 H
1 93 48 -- 0 Ph H 1 94 49 -- 0 Ph H 2 95 50 -- 0 Ph H 3 96 51
6-NH.sub.2 1 97 H 1 98 52 6-NH.sub.2 1 99 H 2 100 53 6-NH.sub.2 1
101 H 3 102 54 -- 0 103 H 1 104 55 -- 0 105 H 1 106 56 -- 0 107 H 1
108 57 -- 0 109 H 1 110 58 -- 0 111 H 1 112 59 -- 0 113 H 1 114 60
-- 0 115 H 1 116 61 -- 0 117 H 1 118 62 -- 0 119 H 1 120 63 -- 0
121 H 1 122 64 -- 0 123 H 1 124 65 -- 0 125 H 1 126 66 -- 0 127 H 1
128 67 -- 0 129 H 1 130 68 -- 0 131 H 1 132 69 -- 0 133 H 1 134 70
-- 0 135 H 1 136 71 -- 0 137 H 1 138 72 -- 0 139 H 1 140 73 -- 0
141 H 1 142 74 -- 0 143 H 1 144 75 -- 0 145 H 1 146 76 -- 0 147 H 1
148 77 -- 0 149 H 1 150 78 -- 0 151 H 1 152 79 -- 0 153 H 1 154 80
-- 0 155 H 2 156 81 -- 0 157 H 3 158 82 -- 0 159 --CO.sub.2- t- Bu
1 160 83 -- 0 161 H 1 162 84 6-NH.sub.2 1 163 H 1 164 85 -- 0 Ph h
1 165 86 -- 0 166 --CO.sub.2- t- Bu 1 167 87 -- 0 168 H 1 169 88 --
0 170 H 1 171 89 -- 0 172 H 1 173 90 -- 0 174 H 1 175 91 -- 0 176 H
1 177 92 -- 0 178 H 1 179 93 -- 0 180 H 1 181 94 -- 0 182 H 1 183
95 -- 0 184 H 1 185 96 -- 0 186 H 1 187 97 -- 0 188 H 1 189 98 -- 0
190 H 1 191 99 -- 0 192 H 1 193 100 -- 0 194 H 1 195 101 -- 0 196 H
1 197 102 -- 0 198 H 1 199 103 -- 0 200 H 1 201 104 -- 0 202 H 1
203 105 -- 0 204 H 1 205 106 -- 0 206 H 1 207 107 4-OH 1 Ph H 1 208
108 6-OH 1 209 H 1 210 109 4-CN 1 Ph H 1 211 110 2-Me 1 Ph H 1 212
111 3-Et 1 Ph H 1 213 112 3-CF.sub.3 1 Ph H 1 214 113 3-NH.sub.2 1
Ph H 1 215 114 3-NH--Me 1 Ph H 1 216 115 3-N(Et).sub.2 1 Ph H 1 217
116 4-OMe 1 Ph H 1 218 117 2,3,5,6-tetra-Cl 4 Ph H 1 219 118 4-OEt
1 Ph H 1 220 119 4-O-cyc-Pr 1 Ph H 1 221 120 2,3,4,5,6-penta-F 5 Ph
H 1 222 121 2,4-di-Cl 2 Ph H 1 223 122 2,4-di-Me 2 Ph H 1 224 123
2,4-di-Cl 2 Ph --CO.sub.2-t- Bu 1 225 124 2,4,5-tri-Cl 3 Ph H 1 226
125 3-CONH-i-Bu 1 Ph H 1 227 126 2,4-di-Me-6-Cl 3 Ph H 1 228 127
229 1 Ph H 1 230 128 3-NO.sub.2 1 Ph H 1 231 129 2-Cl 1 Ph H 1 232
130 4-SMe 1 Ph H 1 233 131 3-SO.sub.2Me 1 Ph H 1 234 132
4-O--C(.dbd.O)Me 1 Ph H 1 235 133 4-C(.dbd.O)Me 1 Ph H 1 236 134
3-CO.sub.2H 1 Ph H 1 237 135 3-NH-SO.sub.2Me 1 Ph H 1 238 136
4-NH-C(.dbd.O)Me 1 Ph H 1 239 137 -- 0 240 H 1 241 138 -- 0 242 H 1
243 139 -- 0 244 H 1 245 140 2-Me 1 246 H 1 247 141 -- 0 248 H 1
249 142 -- 0 250 H 1 251 143 -- 0 252 H 1 253 144 -- 0 254 H 1 255
145 -- 0 256 H 1 257 146 -- 0 Ph CO.sub.2- t- Bu 1 258 147
6-NH.sub.2 1 259 CO.sub.2Me 1 260 148 -- 0 Ph CO NH.sub.2 1 261 149
-- 0 Ph Me 1 262 150 6-NH.sub.2 1 263 Et 1 264 151 -- 0 265 CO Me 1
266 152 6-NH.sub.2 1 267 H 1 268 153 -- 0 269 H 1 270 154 -- 0 271
H 1 272 155 -- 0 273 H 1 274 156 -- 0 275 H 1 276 157 -- 0 277 H 1
278 158 -- 0 279 H 1 280 159 -- 0 281 H 1 282 160 -- 0 283 H 1 284
161 -- 0 285 H 1 286 162 -- 0 287 H 2 288 163 -- 0 289 H 2 290 164
-- 0 291 H 1 292 165 -- 0 293 H 1 294 166 -- 0 295 H 2 296 167 -- 0
297 H 1 298 168 -- 0 299 H 1 300 169 -- 0 301 H 1 302 170 -- 0 303
H 1 304 171 -- 0 305 H 1 306 172 -- 0 307 H 1 308 173 -- 0 309 H 1
310 174 -- 0 311 H 1 312 175 -- 0 313 H 2 314 176
2-oxo-3-CH.sub.3-- 2 315 H 1 316 177 -- 0 317 H 1 318 178
3,5-Cl.sub.2-- 2 319 H 1 320 179 4-Ph 1 Ph H 1 321 180 322 1 Ph H 1
323 181 324 1 Ph H 1 325 182 326 1 Ph H 1 327 183 4-Br 1 Ph H 1 328
184 3-l 1 Ph H 1 329 185 3-CF.sub.3CF.sub.2-- 1 Ph H 1 330 186
4-CH.sub.2.dbd.CHCH.sub.2-- 1 Ph H 1 331 187 4-t-Bu- 1 Ph H 1 332
188 4-n-hexyl- 1 Ph H 1 333 189 4-n-docecyl- 1 Ph H 1 334 190
2-CF.sub.3(CH.sub.2).sub.3-- - 1 Ph H 1 335 191 336 1 Ph H 1 337
192 338 1 Ph H 1 339 193 340 1 Ph H 1 341 194 342 1 Ph H 1 343 195
344 1 Ph H 1 345 196 346 1 Ph H 1 347 197
4-CH.sub.3OCH.sub.2CH.sub.2N(Me)-- 1 Ph H 1 348 198 3-Ph-NH-- 1 Ph
H 1 349 199 350 1 Ph H 1 351 200 352 1 Ph H 1 353 201 -- 0 354 H 1
355 202 -- 0 356 H 1 357 203 -- 0 358 H 1 359 204 -- 0 360 H 1 361
205 -- 0 362 H 1 363 206 -- 0 364 H 1 365 207 2-Me 1 366 H 1 367
208 -- 0 368 H 1 369 209 -- 0 370 H 1 371 210 2-Me 1 372 H 1 373
211 2-Me-- 1 374 H 1 375 212 2-Me-- 1 376 H 1 377 213 2-Me 1 378 H
1 379 214 -- 0 380 H 1 381 215 -- 0 382 H 1 383 216 -- 0 384 H 1
385 217 -- 0 386 H 1 387 218 -- 0 388 H 1 389 219 5-Me 1 390 H 1
391 220 -- 0 392 H 1 393 221 -- 0 394 H 1 395 222 -- 0 396 H 1 397
223 5-Me-- 1 398 H 1 399 224 5-Me-- 1 400 H 1 401 225 -- 0 402 H 1
403 226 -- 0 404 H 1 405 227 -- 0 406 H 1 407 228 -- 0 408 H 1 409
229 -- 0 410 H 1 411 230 -- 0 412 H 1 413 231 5-Me 1 414 H 1 415
232 -- 0 416 H 1 417 233 -- 0 418 H 1 419 234 -- 0 420 H 1 421 235
-- 0 422 H 1 423 236 -- 0 424 H 1 425 237 -- 0 426 H 1 427 238 -- 0
428 H 1 429 239 -- 0 430 H 1 431 240 H 0 432 H 1 433 241 3-Me 1 434
H 1 435 242 -- 0 436 H 1 437 243 -- 0 438 H 1 439 244 -- 0 440 H 1
441 245 3-Me 1 442 H 1 443 246 -- 0 444 H 1 445 247 3-Me 1 446 H 1
447 248 3-Me 1 448 H 1 449 249 6-NH.sub.2 1 450 H 1 451 250
6-NH.sub.2 1 452 H 1 453 251 6-NH.sub.2 1 454 H 2 455 252
2-NH.sub.2 1 456 H 1 457 253 2-NH.sub.2 1 458 H 1 459 254
2-NH.sub.2 1 460 H 1 461 255 2-NH.sub.2 1 462 H 1 463 256
2-NH.sub.2 1 464 H 2 465 257 2-NH.sub.2 1 466 H 2 467 258
4-NH.sub.2 1 468 H 1 469 259 4-NH.sub.2 1 470 H 1 471 260
4-NH.sub.2 1 472 H 1 473 261 4-NH.sub.2 1 474 H 2 475 262
4-NH.sub.2 1 476 H 2 477 263 4-NH.sub.2 1 478 H 2 479 264 -- 0 480
H 1 481 265 -- 0 482 H 1 483 266 -- 0 484 H 1 485 267 -- 0 486 H 1
487 268 -- 0 488 H 1 489 269 -- 0 490 H 1 491 270 -- 0 492 H 1 493
271 -- 0 494 H 1 495 272 -- 0 496 H 1 497 273 -- 0 498 H 1 499 274
-- 0 500 H 2 501 275 -- 0 502 H 2 503 276 -- 0 504 H 2 505 277 -- 0
506 H 1 507 278 -- 0 508 H 2 509 279 -- 0 510 H 1 511 280 -- 0 512
H 2 513
[0143] The present invention includes compounds of Formula I
wherein Y is halo; R.sup.6; SR.sup.1;
S(O).sub.b-phenyl-CO.sub.2R.sup.1; or phenyl optionally fused to
one or two phenyl rings or to a 5- or 6-membered heterocycle
containing one or more heteroatom each independently selected from
N, S, and O; or a 5- or 6-membered heterocycle containing one or
more heteroatom each independently selected from N, S, and O,
optionally fused to a phenyl ring; each cyclic moiety being
optionally substituted with one or more substituents independently
selected from COR.sup.2, halo, NO.sub.2, OR.sup.1, R.sup.1,
SR.sup.1, SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
C.sub.1-C.sub.10COR.sup.2, phenyl, or tetrazolo.
[0144] Another set of compounds of Formula I includes those
compounds wherein Y is phenyl optionally fused to one or two phenyl
rings or to a 5- or 6-membered heterocycle containing one or more
heteroatom independently selected from N, S, and O; or a 5- or
6-membered heterocycle containing one or more heteroatom each
independently selected from N, S, and O, optionally fused to a
phenyl ring; each cyclic moiety being optionally substituted with
one or more substituents independently selected from COR.sup.2,
halo, NO.sub.2, OR.sup.1, R.sup.1, SR.sup.1,
SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
C.sub.1-C.sub.10COR.sup.2, phenyl, or tetrazolo; and d is 1 or
2.
[0145] Another set of compounds of Formula I includes those
compounds wherein Y is phenyl optionally fused to one or two phenyl
rings or to a 5- or 6-membered heterocycle containing one or more
heteroatom each independently selected from N, S, and O; or a 5- or
6-membered heterocycle containing one or more heteroatom each
independently selected from N, S, and O, optionally fused to a
phenyl ring; each cyclic moiety being optionally substituted with
one or more substituents independently selected from COR.sup.2,
halo, NO.sub.2, OR.sup.1, R.sup.1, SR.sup.1,
SO.sub.2NR.sup.1R.sup.7, NR.sup.1R.sup.1,
C.sub.1-C.sub.10COR.sup.2, phenyl, or tetrazolo; d is 1 or 2; and
Ar is phenyl optionally fused to a 5- or 6-membered heterocycle
containing one or more heteroatoms each independently selected from
O, S, and N; or a 5- or 6-membered heterocycle containing one or
more heteroatoms each independently selected from N, S, and O,
optionally fused to phenyl.
[0146] Another set of compounds of Formula I includes those
compounds wherein Y is phenyl optionally fused to one or two phenyl
rings or to a 5- or 6-membered heterocycle containing one or more
heteroatom each independently selected from N, S, and O; or a 5- or
6-membered heterocycle containing one or more heteroatom each
independently selected from N, S, and O, optionally fused to a
phenyl ring; each cyclic moiety being optionally substituted with
one or more substituents independently selected from COR.sup.2
halo, OR.sup.1, R.sup.1 or NR.sup.1R.sup.1; d is 1; Ar is phenyl or
a 5- or 6-membered heterocycle containing one or more N atoms; and
a is 0, 1, 2, or 3.
[0147] In addition, the present invention specifically includes the
following compounds:
[0148]
2-[4-(ethoxycarbonyl)phenoxy]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyri-
dinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid
(Example 197);
[0149]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid (Example 211);
[0150]
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]benzoyl}-2-methylbenzenesulfonamide
(Example 91);
[0151]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid (Example 183);
[0152]
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]benzoyl}-4-methoxybenzenesulfonamide
(Example 92);
[0153]
N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]benzoyl}-1-propanesulfonamide (Example
97);
[0154]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(4-methoxybenzoyl)benzenesulfonamide
(Example 300);
[0155]
N-(2-cyano-4-nitrophenyl)-3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridiny-
l)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide
(Example 259);
[0156]
2-(4-chlorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example
194);
[0157]
N-(4,6-dimethoxy-2-pyrimidinyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-py-
ridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluorometho-
xy)benzenesulfonamide (Example 274);
[0158]
2-(4-fluorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example
193);
[0159]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(3-methoxybenzoyl)benzenesulfonamide
(Example 293);
[0160]
4-fluoro-N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-
methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}benzenesulfonamide
(Example 295);
[0161]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-(4-methylphenoxy)benzoic acid (Example
195);
[0162]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid (Example
213);
[0163]
3-chloro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}met-
hyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 124);
[0164]
N-(4-fluorobenzoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide
(Example 295);
[0165]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-3-methoxybenzoic acid (Example 125);
[0166]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-phenoxybenzoic acid (Example 192);
[0167]
N-(4-cyanophenyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-
amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulf-
onamide (Example 262);
[0168]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)-2-(trifluoro-
methoxy)benzenesulfonamide (Example 275);
[0169]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(3,3,3-trifluoropropanoyl)benzenesulfonamide
(Example 284);
[0170]
2-hydroxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}me-
thyl)-3,4-dihydro-2H-15 chromen-6-yl]benzoic acid (Example
180);
[0171]
3-((1R)-2-{[((2R)-6-{4-[({[(4-fluorophenyl)amino]carbonyl}amino)sul-
fonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyr-
idine (Example 327);
[0172]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide
(Example 249);
[0173]
N-benzoyl-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}me-
thyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide (Example
294);
[0174]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-propoxybenzoic acid (Example 186);
[0175]
N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)--
3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)-4-methoxybenzenesulfona-
mide (Example 80);
[0176]
3-((1R)-1-hydroxy-2-{[((2R)-6-{4-[({[(4-methylphenyl)amino]carbonyl-
}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)pyr-
idine (Example 326);
[0177]
3-((1R)-2-{[((2R)-6-{4-[({[(4-chloro-2-methylphenyl)amino]carbonyl}-
amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxy-
ethyl)pyridine (Example 330);
[0178]
N-(ethoxyacetyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]a-
mino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide
(Example 286);
[0179]
N-(3,3-dimethylbutanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl-
)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide
(Example 287);
[0180]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide
(Example 268);
[0181]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-[4-(methylsulfonyl)phenoxy]benzoic acid
(Example 198);
[0182]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-3-methylbenzoic acid (Example 88);
[0183]
4-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid (Example 215);
[0184]
N-(2,2-dimethylpropanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridiny-
l)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide
(Example 292);
[0185]
3-[(1R)-2-({[(2R)-6-(4-{[(anilinocarbonyl)amino]sulfonyl}phenyl)-3,-
4-dihydro-2H-chromen-2-yl]methyl}amino)-1-hydroxyethyl]pyridine
(Example 328);
[0186]
2-ethoxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}met-
hyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 185);
[0187]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)benzenesulfon-
amide (Example 273);
[0188]
3-{(1R)-2-[({(2R)-6-[4-({[(cyclohexylamino)carbonyl]amino}sulfonyl)-
phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]-1-hydroxyethyl}pyridine
(Example 329);
[0189]
N-(cyclopropylcarbonyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)-
ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide
(Example 285);
[0190]
2-chloro-5-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-
amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example
122);
[0191]
4-[(4-[R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,-
4-dihydro-2H-chromen-6-yl]benzoic acid (Example 148);
[0192]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-methylbenzoic acid (Example 149);
[0193]
2-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}met-
hyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 150);
[0194]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-3-propoxybenzoic acid (Example 130);
[0195]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-isopropoxybenzoic acid (Example
188);
[0196]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide
(Example 265);
[0197]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-(4-methoxyphenoxy)benzoic acid (Example
196);
[0198]
3-(cyclopropylmethoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)e-
thyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid
(Example 132);
[0199]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]benzenesulfonamide (Example 325);
[0200]
5-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-4'-methyl-1,1'-biphenyl-2-carboxylic acid
(Example 205);
[0201]
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide (Example
319);
[0202]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(3-pyridinyl)benzenesulfonamide (Example
253);
[0203]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-methoxybenzoic acid (Example 184);
[0204]
4-chloro-N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-
methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide
(Example 320);
[0205]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-3-isobutoxybenzoic acid (Example 133);
[0206]
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}methanesulfonamide (Example
321);
[0207]
3-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid (Example 216);
[0208]
3-[(1E)-1-hexenyl]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl-
]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example
128);
[0209]
3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide
(Example 261);
[0210]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2-(2-methoxyethoxy)benzoic acid (Example
187);
[0211]
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4--
dihydro-2H-chromen-6-yl]-2,6-dimethylbenzoic acid (Example
121);
[0212]
4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 385);
[0213]
3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 386);
[0214]
(1R)-1-(6-amino-3-pyridinyl)-2-[({(2R)-6-[4-(1H-tetraazol-5-yl)phen-
yl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]ethanol (Example
384);
[0215]
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]phenyl}-3-phenyl-1,2I5,3I5,4-thiatriazole-2-car-
boxylic acid (Example 166);
[0216]
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]phenyl}-2-furoic acid (Example 159);
[0217]
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid
(Example 154);
[0218]
5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]phenyl}-3-thiophenecarboxylic acid
(Example 156);
[0219]
4-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid
(Example 157);
[0220]
6-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid (Example 151);
[0221]
5-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid (Example 142);
[0222]
2-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]-4-pyridinecarboxylic acid (Example
158);
[0223]
1-({[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}me-
thyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}amino)cyclopropanecarboxylic
acid (Example 366); and
[0224]
4-[(2R)-2-({[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}methyl)-3-
,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 344).
[0225] Representative salts of the compounds of Formula I include
the conventional non-toxic salts and the quaternary ammonium salts
which are formed, for example, from inorganic or organic acids or
bases by means well known in the art. For example, such acid
addition salts include acetate, adipate, alginate, ascorbate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate, cinnamate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate,
mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oxalate, pamoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.
[0226] Base salts include alkali metal salts such as potassium and
sodium salts, alkaline earth metal salts such as calcium and
magnesium salts, and ammonium salts with organic bases such as
dicyclohexylamine salts and N-methyl-D-glucamine. Additionally,
basic nitrogen containing groups may be quaternized with such
agents as lower alkyl halides such as methyl, ethyl, propyl, and
butyl chlorides, bromides and iodides; dialkyl sulfates like
dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl and strearyl
chlorides, bromides and iodides, aralkyl halides like benzyl and
phenethyl bromides and others.
[0227] The esters in the present invention are non-toxic,
pharmaceutically acceptable esters such as alkyl esters such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters.
Additional esters such as phenyl-C.sub.1-C.sub.5 alkyl may be used,
although methyl ester is preferred. The compound of Formula I may
be esterified by a variety of conventional procedures including
reacting the appropriate anhydride, carboxylic acid, or acid
chloride with the alcohol group of the Formula I compound. The
appropriate anhydride is reacted with the alcohol in the presence
of an acylation catalyst such as 1,8-bis[dimethylamino]naphthale-
ne or N,N-dimethylaminopyridine. An appropriate carboxylic acid may
be reacted with the alcohol in the presence of a dehydrating agent
such as dicyclohexylcarbodiimide,
1-[3-dimethylaminopropyl]-3-ethylcarbodiimide or other water
soluble dehydrating agents which are used to drive the reaction by
the removal of water, and optionally, an acylation catalyst.
Esterification may also be reached using the appropriate carboxylic
acid in the presence of trifluoroacetic anhydride and optionally,
pyridine, or in the presence of N,N-carbonyldiimidazole with
pyridine. Reaction of an acid chloride with the alcohol may be
carried out with an acylation catalyst such as 4-DMAP or
pyridine.
[0228] Sensitive or reactive groups on the compound of Formula I
may need to be protected during any of the above methods for
forming esters, and protecting groups may be added and removed by
conventional methods well known in the art.
[0229] One skilled in the art would readily know how to
successfully carry out these as well as other methods of
esterification of alcohols.
[0230] The compounds of this invention may, either by nature of
asymmetric centers or by restricted rotation, be present in the
form of isomers. Any isomer may be present in the (R)-, (S)-, or
(R,S) configuration, preferably in the (R)- or (S)-configuration,
whichever is most active. The configurational isomers of Formula I,
in which both the hydroxyl group attached to the side chain
containing the Ar--X-- moiety and the (CH.sub.2)d group attached to
the dihydrochromenyl ring are above the plane, as depicted below,
are preferred. 514
[0231] All isomers, whether separated, pure, partially pure, or in
racemic mixture, of the compounds of this invention are encompassed
within the scope of this invention. The purification of said
isomers and the separation of said isomeric mixtures may be
accomplished by standard techniques known in the art.
[0232] Geometric isomers by nature of substituents about a double
bond or a ring may be present in cis (=Z-) or trans (=E-) form, and
both isomeric forms are encompassed within the scope of this
invention.
[0233] The particular process to be utilized in the preparation of
the compounds of this invention depends upon the specific compound
desired. Such factors as the selection of the specific Ar and Y
moieties and the specific substituents on the various moieties, all
play a role in the path to be followed in the preparation of the
specific compounds of this invention. These factors are readily
recognized by one of ordinary skill in the art.
[0234] For synthesis of any particular compound, one skilled in the
art will recognize that the use of protecting groups may be
required for the synthesis of compounds containing certain
substituents. A description of suitable protecting groups and
appropriate methods of adding and removing such groups may be found
in: Protective Groups in Organic Synthesis, Second Edition, T. W.
Greene, John Wiley and Sons, New York, 1991. For example, after
preparation of a compound according to Reaction Scheme 1, in order
to enable purification of the end product by, for example, flash
chromatography, compounds of Formula I wherein R.sup.3 is H, may be
selectively protected, for example, as a carbamate derivative
obtained by, for example, treatment with a reagent such as
di-tert-butyl dicarbonate or other means known in the art. After
purification, the carbamate group can easily be removed by
treatment with an acid such as HCI or trifluoroacetic acid by means
known in the art.
[0235] In the Reaction Schemes below, one skilled in the art will
recognize that reagents and solvents actually used may be selected
from several reagents and solvents well known in the art to be
effective equivalents. When specific reagents or solvents are shown
in a Reaction Scheme, therefore, they are meant to be illustrative
examples of conditions desirable for the execution of that
particular Reaction Scheme. Abbreviations not identified in
accompanying text are listed later in this disclosure under
"Abbreviations and Acronyms."
[0236] General Methods of Preparation of Formula I Compounds
[0237] In general, Formula I compounds may be prepared by standard
techniques known in the art and by known processes analogous
thereto. In particular, three such standard methods may be used,
the selection of which may be based, among other considerations,
upon the availability of the required individual starting
materials. These three methods are illustrated in Reaction Schemes
1, 2, and 3 below.
[0238] The compounds of Formula I where each variable may be any
moiety within that variable's definition may be synthesized
according to Reaction Scheme 1 wherein an appropriate epoxide 1a or
chlorohydrin 1b (preparation of 1a is described in WO 99/32475) is
coupled with the appropriate amine 2 (preparation of 2 is described
below in Reaction Schemes 12, 13, and 14). This reaction of
Reaction Scheme 1 is typically carried out in an aprotic solvent
such as dimethyl sulfoxide, dimethyl formamide, acetonitrile, or in
an alcohol such as ethanol, isopropanol, or propanol at temperature
from about -10.degree. C. to reflux. Compounds in which R.sup.3 is
other than hydrogen may be prepared by reaction of compound I in
which R.sup.3 is H, by selective N-alkylation of N-acylation
reactions with known compounds of formula R.sup.3-halo (where
R.sup.3 is acyl or alkyl) or [R.sup.3].sub.2O (where R.sup.3 is
acyl). Protection of the hydroxyl group, for example as a TBDMS
ether, may be required prior to N-alkylation reactions;
O-deprotection is carried out under standard conditions well known
in the art. 515
[0239] Alternatively, Formula I compounds, where each variable may
be any moiety within that variables definition, except that d=1,
may be prepared by a reductive amination as shown in Reaction
Scheme 2. Reaction of an aldehyde of Formula 4 (preparation
described below in Reaction Scheme 9) with an amino alcohol of
Formula 3 (preparation described in WO 98/32475) followed by
reduction gives the desired transformation to Formula Ia compounds.
Compounds in which R.sup.3 is other than hydrogen may be prepared
by reaction of compound Ia in which R.sup.3 is H by selective
N-alkylation or N-acylation reactions with known compounds of
formula R.sup.3-halo (where R.sup.3 is alkyl or acyl) or
[R.sup.3].sub.2O (where R.sup.3 is acyl). Protection of the
hydroxyl group, for example, as a TBDMS ether, may be required
prior to N-alkylation reactions. O-deprotection is carried out
under standard conditions well known in the art. 516
[0240] A third general route to Formula I compounds, where each
variable may be any moiety within that variable's definition except
that d=1, is shown in Reaction Scheme 3. An amino alcohol 3 and a
carboxylic acid 5 (preparation described in Reaction Schemes 10 and
11) are coupled to provide an amide of Formula 6. Reduction of the
Formula 6 amides with an appropriate reagent such as
borane-dimethylsulfide complex provides the Formula I compounds
where R.sup.3 is H. Formula I compounds in which R.sup.3 is other
than H may be similarly prepared as described above for Reaction
Schemes 1 and 2. 517
[0241] Reaction Scheme 4 shows that compounds of Formula I or
Formula Ia where Y is any alkenyl, cycloalkenyl, phenyl, or a 5-or
6-membered heterocyclic ring may be prepared from compounds of
Formula I or Formula Ia where Y is a halogen, using the following
additional methods described below. For example, a compound of
Formula I, wherein Y is iodo, may be prepared by Reaction Scheme 1
using corresponding starting materials 2 or 4, where Y is iodo,
each of which may be prepared by Reaction Schemes 12 or 9,
respectively. The resulting Formula I compound is then protected by
standard methods to give a compound of Formula 7a. The compound of
Formula 7a is then converted to the boronic ester 8, which is then
subjected to Suzuki coupling reactions with a halo-Y compound, in
which Y is any alkenyl, cycloalkenyl, phenyl, naphthyl, or a 5-or
6-membered heterocycle to provide Formula 7 compounds as shown in
Reaction Scheme 4. Deprotection of Formula 7 compounds by acid or
fluoride-catalyzed hydrolysis provides the corresponding Formula I
compounds. 518
[0242] The coupling may also be performed in the reverse manner,
that is, a boronic ester derivative 10 prepared from a halophenyl
compound 9 may be added to the iodo compound of Formula 7b, as
shown in Reaction Scheme 5 to give Formula Ib compounds. 519
[0243] Formula I compounds in which Y is an aryl group further
substituted by a S(O).sub.bR.sup.2 or NHS(O).sub.bR.sup.2 group may
be prepared by elaboration of the corresponding Formula 7 compounds
in which Y is an aryl group substituted by CO.sub.2H as shown in
Reaction Scheme 6. 520
[0244] Formula I compounds wherein Y is 521
[0245] and R.sup.1 and R.sup.4 are as described above, may be
prepared by a sequence shown in Reaction Scheme 7. The iodo
compound of Formula 7a may be converted to the carboxylic acid of
Formula 7c by palladium-catalyzed carboxylation. This may then be
coupled with an amino acid using standard peptide synthesis
techniques, deprotected and hydrolyzed to give compounds of Formula
Ic. This method may be repeated to give Formula I compounds where Y
is 522
[0246] by an analogous sequence of reactions performed on the
Formula Ic compounds. 523
[0247] Formula Id compounds of Reaction Scheme 8 may be prepared
according to Reaction Scheme 1 or 3, starting from the known
Formula 5 compound (U.S. Pat. No. 6,051,586) in which Y=NO.sub.2.
Other Formula I compounds wherein Y is NR.sup.1R.sup.1 may be
prepared from the nitro compound of Formula Id by reduction to Ie
followed by dialkylation with the appropriate alkylating agents,
such as R.sup.1-halo, R.sup.1-OTs, or R.sup.1-OMs to If (Reaction
Scheme7). 524
[0248] Reaction Scheme 9 shows how other Formula I compounds in
which Y is S(O).sub.bPh-CO.sub.2R.sup.1 and b is 0 may be prepared
by diazotization of Ie and nucleophilic displacement with a
arylthiol to give arylthioethers of Formula Ih. Oxidation of the
Formula Ih compound with mCPBA or Oxone.RTM. gives the Formula Ii
compound in which Y is --S(O).sub.bPh--CO.sub.2R.sup.1 and b=1 or
the Formula Ij compound in which Y is
--S(O).sub.bPh--CO.sub.2R.sup.1 and b=2, depending on the number of
equivalents of oxidant used in the reaction.
[0249] Formula I compounds in which Y is SR.sup.1 may be similarly
prepared by methods analogous to Reaction Scheme 9, by substituting
HSR.sup.1 in place of the arylthiol in the first step. 525
[0250] The salts and esters of the Formula I compounds of the
invention may be readily prepared by conventional chemical
processes.
[0251] General Method of Preparation of Intermediates
[0252] The starting materials required to carry out the above
described reactions (e.g., epoxides 1a, chlorohydrins 1b, amines 2,
amino alcohols 3, aldehydes 4, and carboxylic acids 5) are in many
cases commercially available or may be readily prepared by methods
known to those skilled in the art. The following routes are
exemplary of such methods, but are not intended to be limiting in
any way.
[0253] The epoxides 1a of Reaction Scheme 1 are commercially
available or may be prepared according to one of the many
procedures described in the literature known to those skilled in
the art. For example, as described in WO 99/32475, the epoxides of
formula 1a may be prepared by the reaction of an aryl methyl ketone
with a selective halogenating agent such as NBS, followed by ketone
reduction with, for example, sodium borohydride to a give a
chlorohydrin 1b (a halo alcohol). Base-catalyzed cyclization of
this alcohol with, for example, potassium carbonate, gives the
epoxides of formula 1a. This method is general for the conversion
of substituted methyl aryl ketones of general formula
(R).sub.a--Ar--C(.dbd.O)CH.sub.3 to the corresponding epoxides of
formula 1a.
[0254] The amino alcohols 3 may be prepared by ring opening of the
epoxides 1a with a nitrogen nucleophile, such as phthalimide, in
the presence of a base to form an intermediate which may be cleaved
or hydrolyzed as described in WO 98/32475. This sequence is general
for conversion of epoxides of formula 1a to the amino alcohols of
formula 3.
[0255] Synthesis of aldehyde starting materials of Formula 4 may be
accomplished from the carboxylic acid of Formula 5 by reduction
with borane followed by oxidation, for example, under Swern
conditions as shown in Reaction Scheme 10. This method is
compatible with a wide variety of Y groups, although in some cases,
a protecting group may also be employed and removed in a subsequent
step. 526
[0256] The carboxylic acids of Formula 5 are generally available
from the known unsubstituted chroman carboxylic acid 5a (WO
99/32476) by various aromatic substitution reactions at the
6-position of the chroman ring and further elaboration of these
products. For example, halogenation (e.g., iodination) of 5a gives
the 6-iodo compound 5b and nitration gives predominantly the
6-nitro analog 5c (U.S. Pat. No. 6,051,586) as shown in Reaction
Scheme 11. 527
[0257] Compounds of Formula 5 where Y is any alkenyl, cycloalkenyl,
phenyl, naphthyl, or a 5- or 6-membered heterocycle may be prepared
by Suzuki coupling of a halo-Y group to an iodo chroman boronic
ester 12 prepared from the iodo chroman acid 5b. 528
[0258] The amine starting materials of Formula 2, in which d=1, are
generally available by standard methods involving conversion of a
carboxylic acid 5 to an amide of Formula 13. Reduction with borane
or further conversion of the Formula 13 amide to the nitrile of
Formula 14 and then reduction by hydrogenation gives the desired
Formula 2a compounds. This sequence is shown in Reaction Scheme 13
for Formula 2 amines wherein d=1 and R.sup.3 is H. Formula 2 amines
in which R.sup.3 is other than H may be prepared by standard
alkylation or acylation methods known in the art. 529
[0259] Formula 2 amines in which d is 2 or 3 may be prepared by
standard homologation sequences of a variety of known intermediates
where d=1. For example, aldehydes of Formula 4 can undergo an alkyl
chain extension according to well known procedures such as that
described by Wittig et al., (Chem. Ber., 2514, 1962) and the
process may be repeated in order to prepare the acetic and
propionic acid homologues of Formula 5 by a method analogous to
Reaction Scheme 13, to provide a variety of Formula 2 amines in
which d=2 or 3.
[0260] Formula 2 amines in which Y is other than hydrogen or halo
may be prepared by palladium-catalyzed coupling reactions on the
N-protected amine of Formula 15a followed by deprotection, as shown
in Reaction Scheme 14. Formula 2 amines prepared in this way in
which the Y group is substituted by an acid, ester, alcohol,
ketone, sulfide, or nitro group may provide additional Formula 2
amines by manipulation of those functional groups by directed
hydrolysis, esterification, reduction, oxidation, or reduction
reactions of the Y group. 530
[0261] Similarly, the amine 2c, after protection, may be directly
substituted at the 6-position of the chroman under Friedel-Crafts
alkylation conditions to provide the compounds of Formula 15 in
which Y is any alkyl or cycloalkyl group. An example of this where
Y is an optionally substituted alkanoic acid group (15c) is shown
in Reaction Scheme 15. 531
[0262] Alcohol intermediates of Formula 11 in which Y is other than
hydrogen or halo may also be prepared from the iodo alcohol 11a by
the previously described Suzuki coupling methodology as shown in
Reaction Scheme 16. This may be accomplished either directly or via
a 4-step sequence involving protection of the alcohol to 16a, for
example, as a t-butyldimethylsilyl ether, conversion of the iodide
to the boronic ester, Suzuki coupling to 16, and finally
deprotection to 11. 532
[0263] The halo-Y compounds used in Reaction Schemes 12, 14, and 16
where halo is iodo, chloro, or bromo and Y is any alkenyl,
cycloalkenyl, phenyl, naphthyl, or a 5- or 6-membered heterocycle,
are either commercially available or synthesized by standard
methods known to those skilled in the art. One such standard method
is direct halogenation of compounds of formula H--Y which are
either commercially available or known in the art. Other methods
include the functional group conversion of HO--Y or H.sub.2N--Y
compounds to halo-Y or TfO--Y compounds by standard substitution
methods.
[0264] Particular illustrations of this are the preparation of
halo-Y compounds of Formula 9b or 9c, where Y represents an oxazole
or a thiazole, prepared by direct halogenation of the unsubstituted
compound or by diazotization of a corresponding amino group as
shown in Reaction Scheme 17. 533
[0265] The heterocyclic intermediates 17 and 18 used to prepare 9b
and 9c are accessible by standard methods from acyclic materials.
Three examples of such heterocycles are shown in Reaction Schemes
18, 19, and 20. 534 535 536
[0266] Using a combination of the above Reaction Schemes and the
knowledge of one skilled in the art, all of compounds of Formula I
may be prepared.
[0267] The following specific examples are presented to further
illustrate the invention described herein, but they are not
intended nor should they be construed to limit the scope of the
invention in any way.
[0268] Abbreviations and Acronyms
[0269] When the following abbreviations are used herein, they have
the following meaning:
[0270] Ac.sub.2O acetic anhydride
[0271] anhy anhydrous
[0272] BH.sub.3 borane
[0273] BOC tert-butyloxycarbonyl
[0274] BTMAICl.sub.2 benzyltrimethylammonium dichloriodate
[0275] n-BuLi n-butyllithium
[0276] t-BuLi t-butyllithium
[0277] Cbz benzyloxycarbonyl
[0278] CDI carbonyldiimidazole
[0279] Celite.RTM. diatomaceous earth filter agent, .RTM.Celite
Corp.
[0280] CI-MS chemical ionization mass spectroscopy
[0281] conc. concentrated
[0282] mCPBA 3-chloroperoxybenzoic acid
[0283] dec. decomposition
[0284] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
[0285] DMAP 4-dimethylaminopyridine
[0286] DME dimethoxyethane
[0287] DMF N,N-dimethylformamide
[0288] DMSO dimethylsulfoxide
[0289] EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
[0290] EtOAc ethyl acetate
[0291] EtOH ethanol (100%)
[0292] Et.sub.2O diethyl ether
[0293] Et.sub.3N triethylamine
[0294] HPLC ES-MS high performance liquid
chromatography-electrospray mass spectroscopy
[0295] HOBT 1-hydroxybenzotriazole hydrate
[0296] KOtBu potassium tert-butoxide
[0297] LiAlH.sub.4 lithium aluminum hydride
[0298] LiBH.sub.4 lithium borohydride
[0299] LiHMDS lithium bis(trimethylsilyl)amide
[0300] MeOH methanol
[0301] MSTFA N-methyl-N-(trimethylsilyl)trifluoroacetamide
[0302] NaBH.sub.4 sodium borohydride
[0303] Na(OAc).sub.3BH sodium triacetoxyborohydride
[0304] NMM 4-methylmorpholine
[0305] Oxone.RTM. potassium peroxymonosulfate, .RTM.E.I. du Pont de
Nemours & Co., Inc.Corp.
[0306] Ph.sub.3P triphenylphosphine
[0307] Pd(dppf)Cl.sub.2
[1,1'-bis(diphenylphosphino)ferrocene]dichloropall- adium(II)
[0308] Pd(PPh.sub.3).sub.4
tetrakis(triphenylphosphine)palladium(0)
[0309] Pd(OAc).sub.2 palladium acetate
[0310] rt room temperature
[0311] TBAF tetrabutylammonium fluoride
[0312] TBDMS tert-butyldimethylsilyl
[0313] TBDMSCl tert-butyldimethylsilyl chloride
[0314] TBDMSOTf tert-butyldimethylsilyl
trifluoromethanesulfonate
[0315] THF tetrahydrofuran
[0316] TFA trifluoroacetic acid
[0317] TLC thin layer chromatography
[0318] Tf trifluoroacetyl
[0319] General Experimental Procedures
[0320] HPLC-electrospray mass spectra (HPLC ES-MS) were obtained
using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump,
a variable wavelength detector, a YMC Pro C18 2.0 mm.times.23 mm
column, and a Finnigan LCQ ion trap mass spectrometer with
electrospray ionization. Gradient elution from 90% A to 95% B over
4 minutes was used on the HPLC. Buffer A was 98% water, 2%
Acetonitrile, and 0.02% TFA. Buffer B was 98% Acetonitrile, 2%
water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using
a variable ion time according to the number of ions in the
source.
[0321] Combinatorial/parallel reactions were carried out in 8-mL
glass vials with Teflon-lined screw caps, or in a polypropylene
reaction block consisting of a 8.times.12 matrix of ninety-six
2.0-mL reaction wells, with each reaction well incorporating a
15-45 micron polyethylene frit. Reaction blocks of this type are
commercially available as FlexChem.TM. reactor blocks from Robbins
Scientific Corporation, Sunnyvale, Calif. The reactor blocks are
sealed with rubber gaskets and a clamping device, and can be heated
with mixing by rotation in an oven (Robbins Scientific).
EXAMPLE 1
[0322] Method A. Preparation of Racemic
2-chloro-1-(3-pyridinyl)ethanol 537
[0323] Sodium borohydride (198 mg, 5.2 mmol) was added to a
0.degree. C. suspension of 2-chloro-1-(3-pyridinyl)ethanone
hydrochloride (500 mg, 2.6 mmol) in ethanol (13 mL). After stirring
at 0.degree. C. for 1 hour, the reaction was adjusted to pH 5 with
1 N aqueous HCl. The solution was concentrated in vacuo to remove
ethanol, and the residue was partitioned between dichloromethane
and water. The organic layer was separated, dried
(Na.sub.2SO.sub.4), and concentrated to provide the title compound
as a crude material that was used directly in following steps:
.sup.1H NMR (CDCl.sub.3) .delta. 8.54 (s, 1 H), 8.48 (d, J=6.2 Hz,
1 H), 7.76 (d, J=7.9 Hz, 1 H), 7.32-7.28 (m, 1 H), 4.95-4.91 (m, 1
H), 3.75-3.62 (m, 2 H).
[0324] Method B: Preparation of
(1R)-2-chloro-1-(3-pyridinyl)ethanol 538
[0325] To a cold (ice bath) solution of 3-(2-chloroacetyl)pyridine
hydrochloride (120 g, 624 mmol) in 500 mL of H.sub.2O, was added
NaHCO.sub.3 (52.8 g, 624 mmol) slowly. After addition, 500 mL of
CH.sub.2Cl.sub.2 was added, and this mixture was stirred for 10
minutes. The organic layer was separated, and the aqueous layer was
washed with CH.sub.2Cl.sub.2 (2.times.150 mL). The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4, the solids
removed by filtration, and solvent removed in vacuo at room
temperature. Anhydrous THF (600 mL) was added to the residue, and
the resulting solution of this crude chloroketone was kept cold
(dry ice) under Ar, until used as described below.
[0326] In an oven-dried 5 L round bottom flask, a solution of
(R)-(+)-2-(.alpha.,.alpha.)-diphenylprolinol (7.8 g, 31.2 mmol) in
600 mL anhydrous THF was stirred at room temperature under Ar and
to it, was added B(OCH.sub.3).sub.3 (4.8 mL, 42 mmol), and the
solution was stirred at room temperature for one hour.
BH.sub.3S(CH.sub.3).sub.2 2M/THF (624 mL, 1.25 mol) was then added.
After the solution was stirred at room temperature for 20 minutes,
the cold chloroketone THF solution was then slowly added at a rate
of 30 mL/hour at room temperature. After the addition, HPLC
analysis showed the reaction was complete providing 97% for the
desired enantiomer of chlorohydrin. MeOH (200 mL) was added slowly
and solution was maintained at a temperature below 20.degree. C.
The reaction mixture was concentrated in vacuo below 40.degree. C.
The product was used without further purification.
EXAMPLE 2
Preparation of (2R)-3,4-dihydro-2H-chromene-2-carboxamide
[0327] 539
[0328] To a solution of (2R)-3,4-dihydro-2H-chromene-2-carboxylic
acid (WO 99/32476) (17.8 g, 0.1 mol) in anhydrous dichloromethane
(170 mL), cooled in an ice-water bath containing 4 drops of
N,N-dimethylformamide, were added oxalyl chloride (13.4 mL, 0.16
mol) via a syringe in 10 minutes under argon. The resulting mixture
was then stirred at room temperature for 15 hours. Solvent was
removed in vacuo to afford the acid chloride cleanly: .sup.1H NMR
(CDCl.sub.3, .delta.): 2.31-2.51 (m, 2H), 2.72-2.91 (m, 2H), 5.01
(t, J=4.2 Hz, 1H), 7.04-7.06 (t, J=8.7 Hz, 2H), 7.03-7.06 (d, J=6.9
Hz, 1H); 7.13-7.18 (t, J=8.1 Hz, 1H).
[0329] To a 2-L 3-necked round-bottomed flask containing ethyl
acetate (633 mL) and ammonium hydroxide (158.2 mL), cooled in an
ice-water bath with vigorous stirring, was added a solution of the
above acid chloride in ethyl acetate (159 mL) dropwise in 15
minutes. The reaction mixture was stirred for additional 20
minutes. The organic layer was separated and washed with water (200
mL), brine (200 mL), and dried over anhydrous sodium sulfate.
Removal of the solvent in vacuo afforded the chroman amide as a
white solid (16.9 g, 95% yield): .sup.1H NMR (CDCl.sub.3, .delta.):
2.01-2.14 (m, 1H), 2.37-2.46 (m, 1H), 2.75-2.95 (m, 2H), 4.53-4.57
(dd, J=9.3, 2.7 Hz, 1H), 5.75 (s, broad, 1H), 6.60 (s, broad, 1H),
6.86-6.93 (m, 2H); 7.07-7.16 (m, 2H); Cl-MS m/z=178
(M+H.sup.+).
EXAMPLE 3
Preparation of (2R)-3,4-dihydro-2H-chromen-2-ylmethylamine
hydrochloride
[0330] 540
[0331] In a dry 1-L 3-necked round-bottomed flask were charged the
amide of Example 2 (16.9 g, 95 mmol) and tetrahydrofuran (100 mL).
The mixture was heated to reflux under argon with stirring to
obtain a clear solution. To this solution was then added
borane/dimethyl sulfide complex (95 mL, 2M in THF) in about 30
minutes. After completion of addition, the reaction was further
refluxed for 1 hour. Additional borane/dimethyl sulfide (80 mL) was
then added to the reaction and the mixture was further refluxed for
1 hour. Heating was removed and replaced with an ice-water bath to
cool the reaction mixture to room temperature. Methanol (43 mL) was
then added to the reaction and it was stirred for 30 minutes. The
reaction mixture was then concentrated in vacuo to remove 140 mL of
liquid. The residue was then treated with ether/HCl (1 M) carefully
to obtain a white suspension which was cooled in an ice-water bath
for 30 minutes before vacuum filtration to obtain the product as a
white powder (16.3 g, 87% yield): .sup.1H NMR (DMSO-d.sub.6,
.delta.): 1.60-1.77 (m, 1H), 2.00-2.08 (m, 1H), 2.65-2.85 (m, 2H),
2.95-3.20 (m, 2H), 4.20-4.30 (m, 1H), 6.75-6.85 (m, 2H), 7.04-7.09
(m, 2H); 8.30 (s, broad, 3H); Cl-MS m/z=164 (M+H.sup.+).
EXAMPLE 4
Preparation of
N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-2,2,2-trifluoroa-
cetamide
[0332] 541
[0333] The amine HCl salt of Example 3 (16.3 g, 82.6 mmol) was
dissolved in 1N aqueous sodium hydroxide solution (91 mL) followed
by extraction with dichloromethane (90 mL.times.3). The combined
organic layer was washed with brine (50 mL) and dried over
anhydrous sodium sulfate. Removal of solvent in vacuo afforded the
free base chroman amine as colorless oil which was mixed with
pyridine (14.2 mL) in dichloromethane (136 mL) under argon.
[0334] To this mixture cooled in an ice-water bath was then added
trifluoroacetic anhydride (23.3 mL) carefully in about 10 minutes.
Cooling bath was removed and the reaction was stirred at room
temperature for 4 hours. It was then poured onto crushed ice (130
g). The organic layer was separated, washed with brine (50 mL), and
dried over anhydrous sodium sulfate. Removal of solvent in vacuo
afforded the product cleanly (19.7 g, 92% yield): .sup.1H NMR
(CDCl.sub.3, .delta.): 1.75-1.86 (m, 1H), 1.99-2.12 (m, 1H),
2.76-2.97 (m, 2H), 3.46-4.26 (m, 3H), 6.80-6.91 (m, 2H), 7.03-7.14
(m, 2H); Cl-MS m/z=260 (M+H.sup.+). The crude product was used for
next step without further purification.
EXAMPLE 5
Preparation of ethyl
(methylsulfanyl)[(2R)-2-(3,3,3-trifluoro-2-oxopropyl)-
-3,4-dihydro-2H-chromen-6-yl]acetate
[0335] 542
[0336] To a solution of
N-[(2R)-3,4-dihydro-2H-chromen-2-ylmethyl]-2,2,2-t-
rifluoroacetamide (Example 4,12.96 g, 50 mmol) and
.alpha.-chloro-2-(methy- lthio) acetate (9.28 g, 55 mmol) in
dichloromethane (75 mL) at 0.degree. C. was slowly added tin(IV)
chloride (55 mL, 1M in CH.sub.2Cl.sub.2) via a syringe. The mixture
became yellow rapidly and precipitation started to form. After
completion of addition, the reaction was stirred at room
temperature for 30 minutes. It was then quenched by addition of
water (100 mL). The organic layer was separated and dried over
anhydrous sodium sulfate and concentrated in vacuo to afford the
crude product as a brown oil (diastereomeric mixture): .sup.1H NMR
(CDCl.sub.3, .delta.): 1.30 (m, 3H), 1.76 (m, 2H), 2.18 (m, 4H),
2.90 (m, 2H), 4.20 (m, 5H), 6.65-6.79 (dd, J=8.1, 7.8 Hz, 1H), 7.18
(m, 2H); Cl-MS m/z=392 (M+H.sup.+). The crude was used without
further purification.
EXAMPLE 6
Preparation of (2R)-6-bromo-3,4-dihydro-2H-chromene-2-carboxylic
Acid
[0337] 543
[0338] Step 1. Preparation of isobutyl
(2R)-6-bromo-3,4-dihydro-2H-chromen- e-2-carboxylate 544
[0339] To dichloromethane (2.2 L) in a round-bottom flask equipped
with a mechanical stirrer, argon gas inlet, and condensor were
charged 255.8 g (1.092 moles, 98% ee) isobutyl
(2R)-3,4-dihydro-2H-chromene-2-carboxylate [prepared by
esterification of (2R)-3,4-dihydro-2H-chromene-2-carboxylic acid
(WO 99/32476)], 156.3 g (0.55 moles)
1,3-dibromo-5,5-dimethylhydanto- in, and 10.49 g (0.109 moles)
methanesulfonic acid. The mixture was stirred in the dark overnight
at room temperature. The reaction mixture was concentrated to 700
ml and the solid hydantoin was filtered and washed once with 50 ml
of dichloromethane. The filtrate was concentrated to afford 355.7 g
(104% crude yield) of a light brown solid, which by H-NMR,
contained residual hydantoin: .sup.1H-NMR (DMSO-d6, 300 MHz)
.delta. 0.85 (d, 6H), 1.86 (m, 1H), 2.13 (m, 2H), 2.59 (m, 1H),
2.81 (m, 1H), 3.90 (d, 2H), 4.98 (t, 1H), 6.80 (d, 1H), 7.22-7.27
(m, 2H); El-MS m/z 312, 314.
[0340] Step 2. Preparation of
(2R)-6-bromo-3,4-dihydro-2H-chromene-2-carbo- xylic Acid 545
[0341] The crude product from step 1 above (1.092 moles) was
dissolved in THF (2.1 L) and charged to a round-bottom flask,
followed by 700 ml of methanol. A solution of LiOH (32.76 g, 1.365
moles) in 700 ml of water was then added over five minutes,
resulting in a 10 degree rise in temperature. The reaction was
stirred for five minutes and a sample analyzed by HPLC indicated
excellent conversion of the starting material. After stirring for
twenty minutes at 50.degree. C., THF and methanol were removed in
vacuo. Water (1.1 L) was added to the resulting solution, which was
then charged to a round-bottom flask. 1.4 L of 1N HCl was slowly
added to the solution to precipitate the product. The mixture was
filtered to obtain 342 g of a white solid that was still wet. Water
was removed by azeotroping with 700 ml of toluene and the compound
was allowed to crystallize upon cooling from refluxing toluene to
room temperature overnight. Upon breaking up the solid crystal, the
reaction mixture was filtered, and the solid was dried in a vacuum
oven overnight to obtain 185 g (66%) of an off-white solid:
.sup.1H-NMR (DMSO-d6, 300 MHz) .delta. 2.07 (m, 2H), 2.61 (m, 1H),
2.78 (m, 1H), 4.81 (t, 1H), 6.77 (d, 1H), 7.21-7.25 (m, 2H), 13.08
(s, 1H).
EXAMPLE 7
[0342] Method A. Preparation of
(2R)-6-iodo-3,4-dihydro-2H-chromene-2-carb- oxylic Acid 546
[0343] (2R)-3,4-Dihydro-2H-chromene-2-carboxylic acid (WO 99/32476)
(26.7 g, 150 mmol), benzyltrimethyl-ammonium dichloroiodate (50.1
g, 144 mmol), and zinc chloride (25.3 g, 186 mmol) were stirred in
glacial acetic acid (500 mL) under argon at room temperature for 18
hours. The solid was removed by vacuum filtration and then washed
with acetic acid (100 mL). The filtrate was concentrated in vacuo
to obtain a solid which was slurried in water (300 mL). The crude
product was obtained as a pink solid after vacuum filtration and
dried (38.3 g, 84%): .sup.1H NMR (DMSO-d.sub.6, .delta.): 1.95-2.10
(m, 1H), 2.60 (m, 1H), 2.70-2.80 (m, 1H), 4.79 (dd, J=6.0, 3.9 Hz,
1H), 6.63 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d,
J=1.8 Hz, 1H). Cl-MS m/z=305 (M+H.sup.+). The crude was used for
next step directly.
[0344] Method B. Preparation of
(2S)-6-iodo-3,4-dihydro-2H-chromene-2-carb- oxylic Acid 547
[0345] Using the same procedure described in for Method A and
(2S)-3,4-dihydro-2H-chromene-2-carboxylic acid as starting
material, the title compound was obtained in 89% yield: .sup.1H NMR
(DMSO-d.sub.6) .delta. 1.95-2.10 (m, 1H), 2.60 (m, 1H), 2.70-2.80
(m, 1H), 4.79 (dd, J=6.0, 3.9 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 7.36
(dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H).
EXAMPLE 8
Preparation of
[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methanol
[0346] 548
[0347] To a solution of
(2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7,
19.5 mmol, 1.0 eq.) in THF (45 mL) at 10.degree. C. was added
dropwise a solution of borane-THF complex (1M in THF, 23.4 mmol,
1.2 eq). The resulting reaction mixture was stirred at 45.degree.
C. for 1.5 hours and was then cooled to 10.degree. C. Next, water
was added followed by saturated NaHCO.sub.3 solution. The resulting
two-phase mixture was separated and the aqueous phase was extracted
with ethyl acetate. The combined organic extracts were washed with
brine, dried over anhydrous sodium sulfate, concentrated to afford
the product as a white solid in quantitative yield that was used
without further purification. GC-MS m/z 290 (M+)
EXAMPLE 9
Preparation of
(2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
[0348] 549
[0349] The crude carboxylic acid of Example 7 (30.4 g, 100 mmol)
and CDI (19.5 g, 120 mmol) were stirred in N,N-dimethylformamide
(300 mL) at room temperature for 2 hours to obtain a yellow
solution. To this solution was then added ammonium acetate (23.1 g,
300 mmol). The resulting mixture was stirred for 3 hours. It was
then cooled in an ice-water bath and water (400 mL) was then added
dropwise to the reaction mixture to obtain a fine white
precipitation which was stirred for 12 hours. The solid was
collected by vacuum filtration, washed with water, and dried by
suction (25.8 g, 85%): .sup.1H NMR (DMSO-d.sub.6, .delta.):
1.75-1.90 (m, 1H), 2.00-2.15 (m, 1H), 2.55-2.80 (m, 2H), 4.43-4.47
(dd, J=8.7, 3.3 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 7.35 (m, 2H).
Cl-MS m/z=304 (M+H.sup.+)
EXAMPLE 10
Preparation of [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine
Hydrochloride
[0350] 550
[0351] The carboxamide of Example 9 (25.0 g, 82.5 mmol) was
suspended in anhydrous tetrahydrofuran (200 mL) at reflux under
argon. To this suspension was then added borane/dimethyl sulfide
complex (83 mL, 2M in THF) dropwise. The reaction became a clear
solution after the addition which was stirred at reflux for 1 hour.
Additional borane reagent (70 mL) was added and the reaction was
further refluxed for 1 hour. Heating was removed and the reaction
was cooled to 0.degree. C. with an ice-water bath. Methanol (38 mL)
was added slowly to quench the reaction. The reaction mixture was
concentrated in vacuo to about 40% of its initial volume. The
residue was then treated with ether/HCl (1 M) to obtain white
precipitate which was filtered, washed with ether, and dried by
suction (11.7 g, 44%): .sup.1H NMR (DMSO-d.sub.6,.delta.): 1.65 (m,
1H), 2.00 (m, 1H), 2.75 (m, 2H), 2.99 (dd, J=13.2, 8.1 Hz, 1H),
3.09-3.1
EXAMPLE 11
Preparation of benzyl
[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarba- mate
[0352] 551
[0353] To a mixture of (R)-6-iodo-chroman-2-methylamine
hydrochloride of Example 10 (3.3 g, 10 mmol) and
benzylchloroformate (1.57 mL, 11 mmol) in tetrahydrofuran (30 mL)
cooled in an ice-water bath was added slowly 1N aqueous sodium
hydroxide in 20 minutes. The resulting mixture was stirred for 1
hour. The organic layer was separated and concentrated in vacuo.
The aqueous layer was extracted with ethyl acetate (50 mL.times.2).
The combined ethyl acetate layer was combined with the above
residue and washed with water (50 mL), brine (50 mL), and dried
over anhydrous sodium sulfate. Removal of the solvent in vacuo
afforded the crude product as a white solid (4.2 g, 99%). .sup.1H
nmr (DMSO d6) .delta. 1.5-1.6 (m, 2H), 1.9, 2.0 (m, 1H), 2.7 (m,
2H), 3.3 (m, 2H), 4.0 (m, 1H), 5.0 (s, 2H), 6.5 (d, 1H), 7.3 (m,
7H), 7.5 (t, 1H).
EXAMPLE 12
Preparation of tert-butyl
[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylc- arbamate
[0354] 552
[0355] [(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine
hydrochloride (Example 10, 3.52 g, 10.83 mmol) was dissolved in THF
(20 mL), and treated with 0.91 g (10.83 mmol) of sodium bicarbonate
in 2 mL of water, followed by the addition of 2.36 g (10.83 mmol)
of di-t-butyldicarbonate. The resulting solution was allowed to
stir for 16 hours at room temperature. At this point the solution
was concentrated in vacuo and the resulting residue was treated
with water and extracted with ethyl acetate. The dried
(Na.sub.2SO.sub.4) ethyl acetate layers were concentrated in vacuo
to obtain 4.02 g of product as a yellowish solid; m/z=389.8
[M+].
EXAMPLE 13
Preparation of
tert-butyl(dimethyl)silyl[(2R)-6-iodo-3,4-dihydro-2H-chrome-
n-2-yl]methyl ether
[0356] 553
[0357] A reaction mixture containing
[(2R)-6-iodo-3,4-dihydro-2H-chromen-2- -yl]methanol (Example 8, 5
g, 17.2 mmol, 1.0 eq), tert-butyldimethylsilyl chloride (20.6 mmol,
1.2 eq), and imidazole (43 mmol, 2.5 eq) in anhydrous DMF (35 mL)
was stirred at 27.degree. C. overnight. The resulting mixture was
then cooled to room temperature, poured into water, and extracted
with diethyl ether. The organic extract was washed with water,
brine, dried over anhydrous sodium sulfate, concentrated, and
purified by medium pressure column chromatography (Biotage 40S
normal phase silica gel column) providing the product in 79% yield;
m/z=405 [MH.sup.=].
EXAMPLE 14
Preparation of
tert-butyl(dimethyl)silyl[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl ether
[0358] 554
[0359] Argon was bubbled through a solution of
tert-butyl(dimethyl)silyl[(-
2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl ether (Example 13,
11.1 mmol, 1.0 eq.) in dioxane (45 mL) for 10 minutes before
Pd(dppf)Cl.sub.2 (0.306 mmol, 0.03 eq.), triethylamine (33.4 mmol,
3.0 eq.), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17.8 mmol,
1.6 eq.) were added. The resulting reaction mixture was stirred at
80.degree. C. overnight. The mixture was then filtered through a
Celite.RTM. pad. The filtrate was concentrated and purified by
medium pressure column chromatography (Biotage 40S normal phase
silica gel column, hexanes:EtOAc=10:1). The product was obtained as
a pale brown waxy solid in 94% yield. MH.sup.+=405.3, retention
time (LC-MS)=4.79 min.
EXAMPLE 15
Preparation of methyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo- ate
[0360] 555
[0361] A solution of methyl 4-iodobenzoate (2.00 g, 7.63 mmol) in
30 mL of dioxane was degassed with argon for 10 minutes. Then, 171
mg (3 mol %) Pd(dppf)Cl.sub.2, 3.27 mL triethylamine, and 1.47 g
(11.45 mmol) pinacolborane were added. The resulting solution was
stirred at 85.degree. C. for 16 hours. The mixture was allowed to
cool to ambient temperature, filtered through a pad of Celite.RTM.,
and concentrated in vacuo to obtain 3.97 g of product which was
used without further purification. m/z=263 [M+H].sup.+
EXAMPLE 16
Preparation of methyl
4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-y-
l]benzoate
[0362] 556
[0363] Method (1)
[0364] Argon was bubbled through a solution of
tert-butyl(dimethyl)silyl[(- 2R)-6-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chrome- n-2-yl]methyl
ether, Example 14, 2.47 mmol, 1.0 eq.) in toluene (60 mL) for 10
minutes. Next, Pd(dppf)Cl.sub.2 (0.164 mmol, 0.07 eq.) and methyl
4-iodobenzoate (3.71 mmol, 1.5 eq.) were added in a single portion.
The resulting reaction mixture was degassed with argon for an
additional 5 minutes before aqueous Na.sub.2CO.sub.3 (2 M, 26 mmol,
10.5 eq.) was added and the solution was heated at 85.degree. C.
overnight. The product mixture was allowed to cool to room
temperature, water was added and the two phase mixture was
extracted with ethyl acetate. The combined organic extracts were
dried over anhydrous sodium sulfate, concentrated, and purified by
medium pressure column chromatography (Biotage 40S normal phase
silica gel column, hexane:ethyl acetate 10:1). The purified product
was dissolved in THF (10 mL) and tetrabutylammonium fluoride (1 M,
5 mL) was added in a single portion. The resulting mixture was
stirred at room temperature for 1 hour. The solvents were
evaporated and the resulting residue was purified by medium
pressure column chromatography (Biotage 40S normal phase silica gel
column, hexanes:EtOAc=5:1 to 2:1). The product was obtained as a
white solid in yield of 46% (two step yield). MH.sup.+=299.2,
retention time (LC-MS)=2.79 min.
[0365] Method (2)
[0366] To a 5-L 3-necked round-bottomed flask were charged
4-methoxycarbonyl phenylboronic acid (72.0 g, 0.4 mol), potassium
carbonate (124.4 g, 0.9 mol), and water (900 mL) to obtain a
suspension. To this suspension was then added a solution of
[(2R)-6-iodo-3,4-dihydro-- 2H-chromen-2-yl]methanol (Example 8,
105.5 g, 0.36 mol) in acetone (720 mL). The resultant mixture
became a near homogeneous solution (internal temperature rose from
20 to 28.degree. C.). Palladium acetate (1.5 g, 0.0067 mol) was
then added in one portion. The reaction mixture was then heated at
65.degree. C. under argon for 2 hours. It turned into a suspension.
Heating was removed and the reaction was allowed to cool to room
temperature. The solid (metallic color) was then collected by
filtration and dried by suction. The crude was then dissolved in
chloroform (2 L) and filtered through a pad of Celite.RTM. (100 g)
under vacuum slowly to remove palladium. Removal of solvent in
vacuo afforded the desired compound as a white solid (90 g, 84%
yield): .sup.1H NMR (CDCl.sub.3, .delta.): 1.82-2.12 (m, 3 H),
2.80-3.02 (m, 2H), 3.75-3.90 (m, 2H), 3.92 (s, 3H), 4.20 (m, 1H),
6.91 (d, J=8.1 Hz, 1H), 7.33 (s, 1 H), 7.37 (dd, J=8.1, 2.7 Hz,
1H), 7.60 (d, J=9 Hz, 2H), 8.06 (d, J=8.7 Hz, 2H).
EXAMPLE 17
Preparation of methyl
3-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-y-
l]benzoate
[0367] 557
[0368] Using essentially the same procedure as Example 16, Method
(1), and substituting the appropriate starting materials, methyl
3-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate was
prepared in yield of 68% (two steps). MH.sup.+=313.1, retention
time (LC-MS)=3.00 min.
EXAMPLE 18
Preparation of methyl
4-((2R)-2-{[(tert-butoxycarbonyl)amino]methyl}-3,4-d-
ihydro-2H-chromen-6-yl) benzoate
[0369] 558
[0370] A solution of methyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl- )benzoate (Example
15, 1.67 g, 6.36 mmol) in 130 mL toluene and 27 mL 1,4-dioxane was
degassed with argon for 10 minutes. tert-Butyl
[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylcarbamate (Example
12, 1.65 g) and 265 mg (3 mol %) Pd(dppf)Cl.sub.2 were then added,
and the solution was degassed with argon for an additional 5
minutes. Finally, 26.5 mL of 2M aqueous sodium carbonate was added
and the solution was stirred at 85.degree. C. for 16 hours. This
mixture was then cooled to ambient temperature, filtered through a
pad of Celite.RTM., and concentrated in vacuo. The product was then
purified by Biotage (100% methylene chloride to 3% MeOH:methylene
chloride) to obtain 1.40 g of product. m/z=397.9 [M+].
EXAMPLE 19
Preparation of methyl 4-[(2
R)-2-(aminomethyl)-3,4-dihydro-2H-chromen-6-yl- ]benzoate
[0371] 559
[0372] To a solution of methyl
4-((2R)-2-{[(tert-butoxycarbonyl)amino]meth-
yl}-3,4-dihydro-2H-chromen-6-yl) benzoate (Example 18, 0.94 g, 2.37
mmol) in 5 mL 1,4-dioxane was added 1 mL of 4M hydrochloric acid in
1,4-dioxane dropwise. The resulting solution was allowed to stir at
room temperature for 16 hours, followed by concentration in vacuo.
At this point, diethyl ether was added and the solid was collected
to provide 587 mg of product as a white solid. m/z=298.2 [MH+].
EXAMPLE 20
Preparation of methyl
4-[(2R)-2-formyl-3,4-dihydro-2H-chromen-6-yl]benzoat- e
[0373] 560
[0374] To a solution of 33 mg (0.425 mmol) dimethyl sulfoxide in 2
mL of methylene chloride at -78.degree. C., was added 0.14 mL
(0.272 mmol) 2M oxalyl chloride. After the solution had stirred at
this temperature for 10 minutes, a solution of 50 mg (0.17 mmol)
methyl
4-[(2R)-2-(hydroxymethyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
(Example 16) in 2 mL of methylene chloride was added dropwise and
the resulting mixture was stirred at -78.degree. C. for an
additional 1.6 hours. At this time, 0.14 mL (1.02 mmol)
triethylamine was added to the mixture slowly, and then it was
allowed to warm to room temperature over 15 minutes. The solution
of desired product was used without further purification.
EXAMPLE 21
Preparation of methyl 4-chloro-2-pyridinecarboxylate
[0375] 561
[0376] To 5020 C. thionyl chloride (14.8 mL, 203.1 mmol, 5.0 eq.)
was added dry N,N-dimethylformamide (0.62 mL, 8.12 mmol, 0.20 eq.).
The solution was stirred for 15 minutes before picolinic acid (5.0
g, 40.6 mmol) was added as a solid. The reaction was immediately
warmed to reflux. After 16 hours at reflux, the mixture was cooled
to room temperature and concentrated by rotary evaporation. The
residue was diluted with toluene and concentrated again. The
resulting oil was poured into a molar excess of methanol and
stirred for 1 hour at room temperature. The methanol was removed by
rotary evaporation, and the resulting crude was partitioned between
ethyl acetate and water. The aqueous layer was adjusted to pH 7
with 1N aqueous sodium hydroxide, and the layers were separated.
The organic layer was washed with brine, dried (MgSO.sub.4), and
concentrated in vacuo to a dark oil. Purification by flash
chromatography on silica gel eluted on a gradient from 100:0 to
70:30 hexanes/ethyl acetate provided the title compound as a pale
orange solid (3.5 g, 50%): .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.61 (d, 1 H), 8.10 (s, 1 H), 7.46 (d, 1 H), 3.98 (s, 3 H);
MS m/z 172.1 (MH.sup.+).
EXAMPLE 22
Preparation of 4-chloro-2-pyridinecarboxamide
[0377] 562
[0378] Using the same procedure described in Example 21 and
substituting aqueous ammonia (28%) for methanol, the title compound
was obtained by filtration (1.91 g, 76% yield): MS m/z 157.8
(MH.sup.+), retention time (LC-MS)=1.08 minutes.
EXAMPLE 23
Preparation of ethyl 2-chloro-3-oxo-3-phenylpropanoate
[0379] 563
[0380] A solution of sulfuryl chloride (12.4 mmol) in toluene (5
mL) was added dropwise via an additional funnel to a solution of
ethyl benzoylacetate (12.4 mmol) in toluene (20 mL) over 5 minutes
at room temperature. The resulting mixture was stirred at room
temperature overnight. Water was added slowly and resulting
two-phase mixture was basified with saturated NaHCO.sub.3 and
extracted with ethyl acetate. The combined organic extracts were
washed with brine, dried over anhydrous sodium sulfate, and
evaporated to afford 2.2 g (84%) of product as a pale yellow oil;
MH.sup.+=227.0, retention time (LC-MS)=2.77 min.
EXAMPLE 24
Preparation of ethyl 2-chloro-4-methyl-3-oxopentanoate
[0381] 564
[0382] Utilizing the method described for Example 23, the product
was obtained in 67% yield (crude). MH.sup.+=193.0, retention time
(LC-MS)=2.45 min.
EXAMPLE 25
Preparation of methyl
2-amino-5-phenyl-1,3-thiazole-4-carboxylate
[0383] 565
[0384] A solution of 25 wt % NaOMe in MeOH (13.4 mmol) was added to
a solution of methyl dichloroacetate (13.4 mmol) and benzaldehyde
(14.8 mmol, 1.1 eq.) in diethyl ether (8 mL) dropwise at 0.degree.
C. The reaction mixture was stirred at 0.degree. C. for 1 hour
before diethyl ether and brine were added. The organic layer was
separated, dried over anhydrous sodium sulfate, and evaporated to
give a crude material which was dissolved in MeOH (16 mL)
containing thiourea (11.4 mmol, 0.85 eq.). The resulting reaction
mixture was heated to reflux for 18 hours. The crude product
mixture was concentrated in vacuo, neutralized with 18M-NH.sub.4OH
at which time the product precipitated as a white solid. The
product was washed with CH.sub.2Cl.sub.2 (2.times.), water and was
collected by filtration to afford 1.88 g (70%) of product;
MH.sup.+=235.1, R.sub.f=0.18 (Hexanes:EtOAc=1:1), retention time
(LC-MS)=1.86 min.
EXAMPLE 26
Preparation of methyl
2-amino-5-isopropyl-1,3-thiazole-4-carboxylate
[0385] 566
[0386] The title compound was prepared according to method of
Example 25 in 88% yield. MH.sup.+=201.0, retention time
(LC-MS)=1.48 min.
EXAMPLE 27
Preparation of ethyl
2-amino-4-phenyl-1,3-thiazole-5-carboxylate
[0387] 567
[0388] A solution of ethyl 2-chloro-3-oxo-3-phenylpropanoate
(Example 23, 9.73 mmol) and thiourea (9.73 mmol) in EtOH (25 mL)
was heated at reflux overnight. The resulting mixture was
concentrated in vacuo, neutralized with 18M-NH.sub.4OH, and
extracted with CH.sub.2Cl.sub.2. The organic phase was washed with
brine, dried over anhydrous sodium sulfate, and concentrated to
afford a yellow solid that was washed with MeOH (3 mL) and dried to
afford the product in 89% yield as a pale yellow solid.
MH.sup.+=249.1, R.sub.f=0.29 (Hexanes:EtOAc=1:1). MH.sup.+=249.1,
retention time (LC-MS)=2.37 min.
EXAMPLE 28
Preparation of ethyl
2-amino-4-isopropyl-1,3-thiazole-5-carboxylate
[0389] 568
[0390] The title compound was prepared according to method of
Example 27 in 65% yield. MH.sup.+=215.1, R.sub.f=0.66
(hexanes:EtOAc=1:1), retention time (LC-MS)=1.98 min.
EXAMPLE 29
Preparation of ethyl 5-phenyl-1,3-oxazole-4-carboxylate
[0391] 569
[0392] To a mixture of ethyl isocyanoacetate (8.74 mmol) and
1,8-diazabicyclo(5.4.0)undec-7-ene (8.84 mmol) in THF (12 mL) was
added a solution of benzoic anhydride (8.84 mmol) in THF (2 mL) at
10.degree. C. with stirring. The resulting mixture was maintained
with vigorous stirring for 18 hours at room temperature. The
solvent was evaporated to afford a residue that was partitioned
between EtOAc and water. The organic extract was dried over
anhydrous sodium sulfate and concentrated to afford an amber oil
which was purified by medium pressure column chromatography
(Biotage 40S normal phase silica gel column, hexanes:EtOAc=6:1 to
4:1 to 2:1). The product was obtained as a clear oil in 42%.
MH.sup.+=218.1, retention time (LC-MS)=2.52 min.
EXAMPLE 30
Preparation of methyl
2-bromo-5-phenyl-1,3-thiazole-4-carboxylate
[0393] 570
[0394] To a dark brown solution of copper(II) bromide (3.85 mmol, 3
eq.) in acetonitrile (5 mL) in a two-neck round-bottomed flask
equipped with a condenser was added tert-butyl nitrite (1.92 mmol,
1.5 eq.) slowly at room temperature. The resulting mixture was
heated to 60.degree. C. at which time a suspension of methyl
2-amino-5-phenyl-1,3-thiazole-4-carboxy- late (Example 25, 1.28
mmol) in acetonitrile (7 mL) was added dropwise. The resulting
reaction mixture was heated at 60.degree. C. for 3 hours, allowed
to cool to room temperature, poured to 1M NaOH aqueous, and
extracted with EtOAc. The organic extracts were dried over
anhydrous sodium sulfate, concentrated, and purified by medium
pressure column chromatography (Biotage 40S normal phase silica gel
column, hexanes:EtOAc=5:1). The product was obtained as a pale
yellow oil in 88%. MH.sup.+=298.0, R.sub.f=0.74
(hexanes:EtOAc=2:1), retention time (LC-MS)=3.01 min.
EXAMPLES 31-33
Preparation of methyl
2-bromo-5-isopropyl-1,3-thiazole-4-carboxylate, ethyl
2-bromo-4-phenyl-1,3-thiazole-5-carboxylate and ethyl
2-bromo-4-isopropyl-1,3-thiazole-5-carboxylate
[0395] Using essentially the same procedure and substituting the
appropriate starting amino compound, the following bromothiazoles
were prepared and characterized according to method of Example
30:
2TABLE 2 Starting Ex. MS Material RT (min. No. Structure [M +
H.sup.+] (Ex. No.) Rf LC-MS) 31 571 264.0 28 0.51 hexanes: EtOAc
6:1 2.83 32 572 312.1 26 0.65 hexanes: EtOAc 6:1 3.46 33 573 278.2
27 0.74 hexanes: EtOAc 6:1 3.54
EXAMPLE 34
Preparation of ethyl 2-iodo-5-phenyl-1,3-oxazole-4-carboxylate
[0396] 574
[0397] To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate
(Example 29, 0.921 mmol, 1 eq.) in THF (7 mL) at -78.degree. C. was
added a solution of lithium bis(trimethylsilyl)amide in THF (1M,
1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was
stirred at -78.degree. C. for 1 hour at which time a solution of
iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a
syringe. The reaction mixture was allowed to warm to room
temperature and stirred at this temperature for 1.5 hours. The
resulting solution was poured onto 10% aqueous NaS.sub.2O.sub.3 (15
mL) and extracted with ethyl acetate. The organic extracts were
washed with brine, dried over anhydrous sodium sulfate,
concentrated in vacuo and purified by medium pressure column
chromatography (Biotage 40S normal phase silica gel column,
hexanes:EtOAc=9:1). The product was obtained as a pale yellow solid
in 82% yield. MH.sup.+=344.0, R.sub.f=0.31 (hexanes:EtOAc=6:1),
retention time (LC-MS)=3.01 min.
EXAMPLE 35
[0398] Method A. Preparation of
(2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide 575
[0399] (1R)-2-Amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S.
Pat. No. 6,051,586) (5.73 g, 27.1 mmol), 1-hydroxybenzotriazole
(6.67 g, 49.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcabodiimide
hydrochloride (9.46 g, 49.3 mmol), and triethylamine (13.8 mL, 9.98
g, 98.7 mmol) were added successively to a stirred solution of
(2R)-6-iodo-3,4-dihydro-2H-chromene- -2-carboxylic acid (Example 7,
Method A, 7.50 g, 24.7 mmol) in dichloromethane (100 mL). The
reaction was stirred for 18 hours and then diluted with
dichloromethane (300 mL). The solution was washed with saturated
aqueous sodium bicarbonate (300 mL) and then the aqueous layer was
back-extracted with dichloromethane (2.times.100 mL). The combined
organic extracts were washed with brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. Flash
chromatography of the residue over silica gel using 5-10%
methanol/ethyl acetate gave the product (7.80 g, 74%) as a white
solid: .sup.1H NMR (acetone-d.sub.6, .delta.): 8.55 (d, J=1.6 Hz, 1
H), 8.44 (dd, J=4.7, 1.6 Hz, 1 H), 7.71 (ddd, J=7.9, 1.8, 1.8 Hz,
1H), 7.59 (s, 1 H), 7.35-7.42 (m, 2 H), 7.27 (dd, J=7.9, 4.7 Hz, 1
H), 6.63 (d, 9.6 Hz, 1 H), 4.98 (d, J=4.2 Hz, 1 H), 4.85-4.93 (m, 1
H), 4.53 (dd, J=8.8, 3.4 Hz, 1 H), 3.38-3.70 (m, 2 H), 2.61-2.91
(m, 4 H), 2.16-2.28 (m, 2 H), 1.85-1.99 (m, 1 H); mass spectroscopy
gave m/z=425.1 [M+H].sup.+.
[0400] Method B. Preparation of
(2S)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethy-
l]-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide 576
[0401] Using the same procedure described in Method A, using
(2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7,
Method B) and (1R)-2-amino-1-(3-pyridinyl)ethanol dihydrochloride
(U.S. Pat. No. 6,051,586), the title compound was obtained as a
white solid in 87% yield. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.47
(d, J=2.2 Hz, 1 H), 8.43 (dd, J=6.6, 1.8 Hz, 1 H), 7.90 (t, J=7.1
Hz, 1 H), 7.69-7.60 (m, 1 H), 7.40-7.37 (m, 2 H), 7.30-7.26 (m, 1
H), 6.66 (d, J=9.1 Hz, 1 H), 5.66 (d, J=4.6 Hz, 1 H), 4.72 (q,
J=5.0 Hz, 1 H), 4.52 (dd, J=8.3, 3.3 Hz, 1 H), 4.12 (dd, J=6.1, 1.8
Hz, 1 H), 3.36-3.32 (m, 1 H), 2.77-2.65 (m, 1 H), 2.58-2.52 (m, 1
H), 2.08-2.00 (m, 1 H), 1.85-1.73 (m, 1 H). LC-MS m/z 425.1
(MH.sup.+), RT=2.07 minutes.
EXAMPLE 36
Method A. Preparation of
(1R)-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl-
]methyl}amino)-1-(3-pyridinyl)ethanol
[0402] 577
[0403] Borane-dimethylsulfide complex (2.0 M in tetrahydrofuran, 46
mL, 92 mmol) was added dropwise (20 minutes) to a cooled (0.degree.
C.) and stirred solution of
(2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3-
,4-dihydro-2H-chromene-2-carboxamide (Example 35, Method A, 7.75 g,
18.3 mmol) in tetrahydrofuran (300 mL). The solution was warmed to
reflux for 1 hour and then cooled to room temperature. The reaction
was quenched with addition of methanol (12 mL) and 2 M hydrochloric
acid (95 mL), and then the resulting solution was heated at reflux
for 1 hour. The reaction was cooled to room temperature and then
the solution was adjusted to pH 9 using 1 M aqueous sodium
hydroxide. The mixture was diluted with brine (500 mL) and the
layers were separated. The aqueous layer was extracted with ethyl
acetate (2.times.200 mL) and then the combined organic extracts
were washed with brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel using 30-50% ethyl acetate/hexane afforded product (6.32
g, 84%) as a waxy yellow solid: .sup.1H NMR (acetone-d.sub.6,
.delta.): 8.59 (d, J=1.9 Hz, 1 H), 8.44 (dd, J=5.0, 1.5 Hz, 1 H),
7.77 (ddd, J=8.0, 1.8, 1.8 Hz, 1 H), 7.25-7.39 (m, 3 H), 6.56 (d,
J=8.4 Hz, 1 H), 4.80 (dd, J=8.4, 4.0 Hz, 1 H), 4.08-4.18 (m, 1 H),
2.67-3.00 (m, 10 H), 1.67-1.82 (m, 1 H); mass spectroscopy gave
m/z=410.9 [M+H].sup.+.
[0404] Method B. Preparation of
(1R)-2-({[(2S)-6-iodo-3,4-dihydro-2H-chrom-
en-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol 578
[0405] Using the same procedure described in Method A using
(2S)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-iodo-3,4-dihydro-2H-chrome-
ne-2-carboxamide (Example 35, Method B), the title compound was
obtained as a crude oil after quench and extractive workup. The
crude material was not purified before carrying on to the next
step. LC-MS m/z 411.3 (MH.sup.+), RT=2.23 minutes.
EXAMPLE 37
[0406] Method A. Preparation of tert-butyl
(2R)-2-hydroxy-2-(3-pyridinyl)e-
thyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
579
[0407] A solution of di-tert-butyl dicarbonate (3.46 g, 15.9 mmol)
in tetrahydrofuran (20+5 mL rinse) was added to a cooled (0.degree.
C.) and stirred solution of
(1R)-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]met-
hyl}amino)-1-(3-pyridinyl)ethanol (Example 36, Method A, 6.20 g,
15.1 mmol) in tetrahydrofuran (75 mL). The mixture was stirred at
0.degree. C. for 1 hour, warmed to room temperature, and stirred
for 18 hours. The solution was concentrated in vacuo and then flash
chromatography of the residue over silica gel using ethyl acetate
gave product (7.23 g, 93%) as a glassy white solid: .sup.1H NMR
(acetone-d.sub.6, .delta.): 8.57 (s, 1 H), 8.46 (s, 1 H), 7.70 (d,
J=7.5 Hz, 1 H), 7.27-7.40 (m, 3 H), 6.57 (d, J=8.5 Hz, 1 H),
4.76-5.11 (m, 2 H), 4.17-4.28 (m, 1 H), 3.42-3.75 (m, 4 H),
2.69-2.90 (m, 1 H), 1.94-2.06 (m, 1 H), 1.58-1.75 (m, 1 H), 1.41
(d, J=7.6 Hz, 9 H); mass spectroscopy gave m/z=510.9
[M+H].sup.+.
[0408] Method B. Preparation of tert-butyl
(2R)-2-hydroxy-2-(3-pyridinyl)e-
thyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
580
[0409] Using the same procedure described in Method A, with
(1R)-2-({[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-(3-pyri-
dinyl)ethanol (Example 36, Method B), the title compound was
obtained (55% overall yield for the reduction to the amine and
protection as the carbamate). LC-MS m/z 511.1 (MH.sup.+), RT=2.59
minutes.
EXAMPLE 38
[0410] Method A. Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)si-
lyl]oxy}-2-(3-pyridinyl]ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]met-
hyl}carbamate 581
[0411] A mixture of tert-butyl
(2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-
-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37,
Method A, 6.35 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9 mmol) and
imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred at room
temperature under argon for 24 hours. The reaction mixture was then
poured into a saturated NaHCO.sub.3 solution (50 mL). The mixture
was extracted with ether (100 mL.times.2). The ether layer was
washed with water (50 mL) and dried over anhydrous sodium sulfate.
Removal of the solvent in vacuo afforded a near white syrup which
was purified by column chromatography (silica gel, hexanes/ethyl
acetate (5/1, v/v)) giving the desired compound as a colorless oil.
LC-MS m/z 625.0 (MH+), RT=4.09 minutes.
[0412] Method B. Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)si-
lyl]oxy}-2-(3-pyridinyl]ethyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-yl]met-
hyl}carbamate 582
[0413] Using the same procedure described in Method A, using
tert-butyl
(2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2S)-6-iodo-3,4-dihydro-2H-chromen-2-
-yl]methyl}carbamate (Example 37, Method B) as starting material,
the title compound was obtained in 65% yield. LC-MS m/z 625.3
(MH.sup.+), RT=3.54 minutes.
EXAMPLE 39
Preparation of
(1R)-2-({[(2R)-6-(3,4-dichlorophenyl)-3,4-dihydro-2H-chrome-
n-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol
[0414] 583
[0415] 3,4-Dichlorophenylboronic acid (34 mg, 0.18 mmol), a
solution of palladium acetate (3 mg, 0.01 mmol) and
triphenylphosphine (12 mg, 0.05 mmol) in toluene (1 mL), and 2 M
aqueous sodium carbonate (1 mL) were added successively to a
solution of tert-butyl (2R)-2-hydroxy-2-(3-pyridi-
nyl)ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
(Example 37, 60 mg, 0.12 mmol) in toluene (2 mL). The mixture was
heated (80.degree. C.) and stirred for 16 hours. After cooling the
reaction was diluted with dichloromethane (5 mL) and the layers
were separated. The organic layer was concentrated in vacuo and the
residue was dissolved in a solution of 4 M hydrogen chloride in
dioxane (4 mL). The solution was stirred for 16 hours and then
concentrated in vacuo. Preparative reverse phase HPLC of the
residue using acetonitrile/water afforded 10.3 mg (20%) of the
desired product (retention time=2.19 min.): .sup.1H NMR
(CD.sub.3OD, .delta.): 8.71 (d, J=2.2 Hz, 1 H), 8.59 (dd, J=5.1,
1.5 Hz, 1 H), 8.11 (ddd, J=7.9, 1.7, 1.7 Hz, 1 H), 7.71 (d, J=2.3
Hz, 1 H), 7.61 (dd, J=7.9, 5.1 Hz, 1 H), 7.37-7.56 (m, 4 H), 6.99
(d, 9.2 Hz, 1 H), 5.22 (dd, J=10.5, 2.9 Hz, 1 H), 4.43-4.54 (m, 1
H), 3.26-3.55 (m, 4 H), 2.87-3.10 (m, 2 H), 2.11-2.22 (m, 1 H),
1.76-1.92 (m, 1 H); mass spectroscopy gave m/z=429.2
[M+H].sup.+.
[0416] Using essentially the same method as described for Example
39 and using Example 37 and the appropriate substituted
phenylboronic acid as starting materials, the following compounds
were prepared and characterized in Table 3.
3TABLE 3 584 HPLC Example MS RT No. Y [M + H.sup.+] (min) 40 585
429.2 2.00 41 586 395.2 2.03 42 587 406.2 1.86 43 588 391.2 1.75 44
589 429.2 2.07 45 590 375.2 1.94 46 591 395.2 1.99 47 592 437.3
2.27 48 593 379.2 1.86 49 594 407.2 1.98 50 595 405.2 1.80 51 596
429.2 2.14 52 597 413.2 2.04 53 598 451.2 1.72 54 599 411.2 2.09 55
600 411.2 2.15 56 601 367.2 1.77 57 602 367.2 1.74 58 603 417.2
2.09 59 604 401.2 2.04 60 605 375.2 1.92 61 606 395.2 1.95 62 607
439.2 2.06 63 608 405.2 1.95 64 609 439.2 2.06 65 610 497.2 2.30 66
611 429.1 2.20 67 612 455.2 1.93 68 613 461.3 2.32 69 614 420.2
1.99
EXAMPLE 70
Preparation of
4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]ox-
y}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,-
4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic Acid
[0417] 615
[0418] Argon was bubbled through a mixture of
(1R)-1-(3-pyridinyl)-2-({[(2-
R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen--
2-yl]methyl}amino)ethanol (Example 81, I, 0.50 g, 0.80 mmol) and
methyl 4-chloro-2-pyridinecarboxylate (Example 21, 0.15 g, 0.88
mmol, 1.1 eq.) in toluene (2 mL), ethanol (2 mL), and 2M aqueous
sodium carbonate (2 mL) for 15 minutes. Triphenylphosphine (0.04 g,
0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol,
0.05 eq.) were added, and the mixture was stirred vigorously under
argon at 85.degree. C. overnight. The reaction was cooled and
filtered through a pad of Celite.RTM. with the aid of ethyl
acetate. The filtrate was transferred to a separatory funnel where
the layers were separated. The organic layer was concentrated in
vacuo to remove excess solvents, and the resulting oil was
dissolved in ethyl acetate. The ethyl acetate solution was
extracted with a 1:1 solution of saturated aqueous sodium
bicarbonate and water. The aqueous layer was adjusted to pH 4 with
1N aqueous HCl, then extracted with chloroform (2.times.). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to provide the title compound as an orange
oil (0.24 g, 48%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.62
(d, 1 H), 8.55 (broad s, 1 H), 8.39 (s, 1 H), 7.78-7.66 (m, 2 H),
7.51-7.48 (m, 1 H), 7.42 (broad s, 2 H), 7.34-7.31 (m, 1 H), 6.82
(dd, 1 H), 5.15-4.97 (m, 1 H), 4.24-4.12 (m, 3 H), 3.76-3.61 (m, 1
H), 3.46-3.30 (m, 1 H), 2.88-2.83 (m, 1 H), 2.05-1.95 (m, 1 H),
1.72-1.62 (m, 2 H), 1.21 (s, 9 H), 0.86 (s, 9 H), 0.03 (s, 3 H),
-0.15 (s, 3 H); MS m/z 620.3 (MH.sup.+).
EXAMPLE 71
Preparation of
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinecarboxylic Acid
[0419] 616
[0420]
4-{[(2R)-2-[([(2R)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-2-(3-
-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihyd-
ro-2H-chromen-6-yl}-2-pyridinecarboxylic acid (Example 70, 29 mg,
0.05 mmol) was stirred in an excess of 4M HCl in dioxane at room
temperature for 18 hours. The volatile components were removed by
rotary evaporation, and the residue was washed with
dichloromethane. After drying under vacuum, the title compound was
collected as the tri-hydrochloride salt (23 mg, 93%): .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 9.07 (broad s, 1 H), 8.90 (d, 1 H),
8.83-8.78 (m, 3 H), 8.49 (d, 1 H), 8.18 (t, 1 H), 7.94-7.89 (m, 2
H), 7.20 (d, 1 H), 5.52-5.46 (m, 1 H), 4.67-4.61 (m, 1 H),
3.76-3.57 (m, 2 H), 3.51-3.39 (m, 2 H), 3.10-3.05 (m, 2 H),
2.29-2.20 (m, 1 H), 1.95-1.83 (m, 1 H); MS m/z 406.2 (MH.sup.+ of
the free base).
EXAMPLE 72
Preparation of methyl
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]ami-
no}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinecarboxylate
[0421] 617
[0422] Argon was bubbled through a mixture of
(1R)-1-(3-pyridinyl)-2-({[(2-
R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen--
2-yl]methyl}amino)ethanol (Example 81, 0.50 g, 0.80 mmol) and
methyl 4-chloro-2-pyridinecarboxylate (Example 21, 0.15 g, 0.88
mmol, 1.1 eq.) in toluene (2 mL), ethanol (2 mL), and 2M aqueous
sodium carbonate (2 mL) for 15 minutes. Triphenylphosphine (0.04 g,
0.16 mmol, 0.2 eq.) and palladium (II) acetate (0.01 g, 0.04 mmol,
0.05 equivalent) were added, and the mixture was stirred vigorously
under argon at 85.degree. C. overnight. The reaction was cooled and
filtered through a pad of Celite.RTM. with the aid of ethyl
acetate. The filtrate was transferred to a separatory funnel where
the layers were separated. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel flushed with ethyl
acetate followed by elution with 95:5 chloroform/methanol. The
coupling product was obtained as a yellow oil (63 mg, 12%); MS m/z
634.3 (MH.sup.+). The intermediate oil was stirred in 4N HCl in
dioxane overnight at room temperature. The reaction was
concentrated in vacuo and the residue was washed with
dichloromethane to provide the title compound as the
tri-hydrochloride salt (32 mg, 77%): .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.51 (broad s, 1 H), 9.36 (broad s, 1 H),
8.95 (s, 1 H), 8.89 (d, 1 H), 8.71 (d, 1 H), 8.62 (d, 1 H), 8.27
(s, 1 H), 8.10-8.06 (m, 1 H), 7.96-7.94 (m, 1 H), 7.70-7.65 (m, 2
H), 6.98 (d, 1 H), 5.42-5.39 (m, 2 H), 4.60-4.55 (m, 1 H), 3.91 (s,
3 H), 3.46-3.30 (m, 4 H), 2.94-2.88 (m, 1 H), 2.16-2.12 (m, 1 H),
1.83-1.68 (m, 1 H); MS m/z 420.1 (MH.sup.+ of the free base).
EXAMPLE 73
Preparation of
trifluoro-N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)et-
hyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)methan-
esulfonamide
[0423] 618
[0424] Into a solution of
4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimeth-
yl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino-
)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-pyridinecarboxylic acid
(Example 70, 113 mg, 0.18 mmol) in dichloromethane (2 mL) was added
trifluoromethylsulfonamide (30 mg, 0.20 mmol, 1.1 eq.),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (42
mg, 0.22 mmol, 1.2 eq.), and N,N-dimethylaminopyridine (22 mg, 0.18
mmol, 1.0 eq.). The solution was stirred overnight at room
temperature before being concentrated in vacuo to remove volatile
components. The crude residue was purified by flash chromatography
on silica gel flushed with ethyl acetate followed by elution with
3:1 ethyl acetate/methanol. The coupling product was obtained as a
yellow oil (36 mg, 27%); MS m/z 751.2 (MH.sup.+). The protected
intermediate was stirred in an excess of 4N HCl in dioxane
overnight at room temperature. The reaction was concentrated in
vacuo, and the residue was washed with dichloromethane to provide
the title compound as the tri-hydrochloride salt (19 mg, 61%):
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 9.11 (s, 1 H), 8.89 (d, 1
H), 8.75-8.60 (m, 2 H), 8.34 (d, 1 H), 8.18 (t, 1 H), 7.92-7.74 (m,
2 H), 7.68-7.54 (m, 1 H), 7.20-7.08 (m, 1 H), 4.70-4.60 (m, 1 H),
3.74-3.59 (m, 5 H), 3.02-2.90 (m, 2 H), 2.24-2.16 (m, 1 H),
1.89-1.77 (m, 1 H); MS m/z 537.1 (MH.sup.+ of the free base).
[0425] By employing the methods described in Example 73 and by
using the compound of Example 70 with the appropriate amide or
sulfonamide as starting materials, the following were similarly
prepared and characterized:
4TABLE 4 619 Example Calculated MS RT (minutes) No. R' Y MW [M +
H.sup.+] LC-MS 74 620 621 418.2 419.2 0.93 75 622 623 480.22 481.2
2.01 76 624 625 516.2 517.2 2.18 77 626 627 482.16 483.1 0.75 78
628 629 510.19 511.2 1.03 79 630 631 562.17 563.2 2.02 80 632 633
574.19 575.2 1.73
EXAMPLE 81
[0426] Method A. Preparation of
(1R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5--
tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}am-
ino)ethanol 634
[0427] According to the procedure of Murata et al., (J. Org. Chem.
62:6458, 1997), Ar was bubbled into a dioxane solution (40 mL) of
(tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{-
[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example
38, Method A, 3.90 g, 6.126 mmol) for 10 minutes. To this solution
was then added Pd(dppf)Cl.sub.2 (100 mg) and Et.sub.3N (4.0 mL),
and then pinacolborane (2.0 mL, 13.78 mmol, Aldrich Chemical Co.)
was added slowly via syringe. The reaction mixture was stirred at
80.degree. C. for 12 hours and allowed to cool to room temperature.
It was filtered through a pad of Celite.RTM. and concentrated in
vacuo to an oily residue. The residue was purified on silica gel
with EtOAc-Hexane (1:4) as the eluant to provide (II) (3.73 g,
97%): .sup.1H NMR (CDCl.sub.3, .delta.): -0.1 (s, 3H), 0.10 (s, 3
H), 0.90 (s, 9 H), 1.32 (s, 12 H), 1.50 (s, 9 H), 1.60-1.80 (m, 1
H), 1.95-2.10 (m, 1 H), 2.80 (dd, 2 H), 3.30-3.50 (m, 2 H),
3.60-3.64 (dd, 1 H), 3.76-3.80(dd, 1 H), 4.20-4.26 (m, 1 H), 5.02
(bs, 1 H), 6.78 (d, 1 H), 7.40 (s, 1 H), 7.50 (m, 2 H), 7.75 (m, 1
H), 8.54 (m, 2 H); m/z=625.4 [M+H].sup.+.
[0428] Method B. Preparation of
(1R)-1-(3-pyridinyl)-2-({[(2S)-6-(4,4,5,5--
tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}am-
ino)ethanol 635
[0429] Using the same procedure described in Method A, with
tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{[(2S)-6-iodo-
-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 38, Method
B), the title compound was obtained in 63% yield. .sup.1H NMR
(DMSO-d.sub.6) .delta. 8.52-8.48 (m, 2 H), 7.72-7.67 (m, 1 H),
7.40-7.32 (m, 3 H), 6.67 (d, J=8.2 Hz, 1 H), 5.09-5.00 (m, 1 H),
4.26-4.16 (m, 1 H), 3.56-3.38 (m, 4 H), 2.76-2.69 (m, 2 H),
1.95-1.89 (m, 1 H), 1.63-1.52 (m, 1 H), 1.25 (s, 9 H), 0.82 (s, 9
H), 0.00 s, 3 H), -0.15 (s, 3 H). LC-MS m/z 625.4 (MH.sup.+),
RT=3.66 minutes.
EXAMPLE 82
Preparation of methyl
2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-buty-
l(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-ch-
romen-6-yl]benzoate
[0430] 636
[0431] Argon gas was bubbled through a solution of (1
R)-1-(3-pyridinyl)-2-({[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 81,
115 mg, 0.184 mmol) in toluene (5 mL) and dioxane (1 mL) for 10
minutes and then Pd(dppf)Cl.sub.2(10 mg) and methyl 2-iodobenzoate
(72 mg, 0.276 mmol, Aldrich Chemical Co.) were added and the
mixture was bubbled with argon for an additional 5 minutes. The
mixture was treated with Na.sub.2CO.sub.3 (1.0 mL of a 2.0 M aq.)
and the bi-phase mixture stirred vigorously under Ar at 85.degree.
C. for 12 hours. The cooled reaction mixture was filtered through a
pad of Celite.RTM. and the filtrate was extracted with EtOAc
(2.times.20 mL). Concentration of the organic extracts in vacuo and
purification on silica gel using a gradient of 20-30% EtOAc/Hexanes
provided the product as colorless oil (61 mg, 52%); .sup.1H NMR
(CDCl.sub.3, .delta.): 0.01 (s, 3H), 0.20 (s, 3 H), 0.99 (s, 9 H),
1.59 (s, 9 H), 1.64-1.82 (m, 1 H), 1.98-2.10 (m, 1 H), 2.80-3.00
(dd, 2 H), 3.40-3.58 (m, 2 H), 3.80 (s, 3 H), 3.80-3.90 (dd, 1 H),
4.20-4.40 (m, 2 H), 5.02 (bs, 1 H), 6.78 (d, 1 H), 7.10 (bs, 2 H),
7.40-7.60 (m, 3 H), 7.90-8.00 (m, 3 H), 8.60-8.80 (m, 2 H); MS:
[M+H].sup.+ 633.3
EXAMPLE 83
Preparation of methyl 2-[(2
R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]am-
ino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
[0432] 637
[0433] A stirred solution of methyl
2-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-
-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-
-dihydro-2H-chromen-6-yl]benzoate (Example 82, 61 mg, 0.096 mmol)
in MeOH (0.50 mL) was treated with HCl in dioxane (1 mL of a 4N
solution in dioxane, Aldrich Chemical Co.) at room temperature and
stirring continued for 60 minutes. The mixture was concentrated in
vacuo and purified on silica gel using a gradient of 5-10%
MeOH/EtOAc to provide 31 mg of product as colorless oil (77%);
.sup.1H NMR (DMSO-d.sub.6, .delta.): 1.65-2.04 (m, 2 H), 2.50-3.10
(m, 6 H), 3.65 (s, 3 H), 4.10 (dd, 1 H), 4.80 (d, 1 H), 6.80 (d, 1
H), 7.00 (bs, 2 H), 7.25-7.40 (m, 3 H), 7.42-7.52 (m, 1 H),
7.78-7.80 (m, 2 H), 8.52 (s, 1 H), 8.60 (s, 1 H); MS: m/z=419.3
[M+H].sup.+.
EXAMPLE 84
Preparation of
2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
[0434] 638
[0435] To a solution of methyl
2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)-
ethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example
83, 60 mg, 0.143 mmol) in THF (0.50 mL) and MeOH (0.50 mL) was
added LiOH (1.0 mL of a 2.0 M aq solution), and the mixture was
stirred at room temperature for 2 hours. The mixture was diluted
with 1.0 mL H.sub.2O and purified via preparative HPLC (gradient of
100:0 0.1% TFA/H.sub.20:acetonitrile to 30:70 0.1%
TFA/H.sub.20:acetonitrile). The peak of interest was collected and
concentrated in vacuo to provide 41 mg of desired final product as
a bis-trifluoroacetic acid (TFA) salt; .sup.1H NMR (DMSO-d.sub.6,
.delta.): 1.68-1.80 (m, 1 H), 2.04-2.18 (m, 1 H), 2.72-2.90 (m, 2
H), 3.22-3.50 (m, 4 H), 4.58 (dd, 1 H), 5.41 (d, 1 H), 6.82 (d, 1
H), 7.02 (d, 1 H), 7.04 (s, 1 H), 7.30-7.40 (m, 2 H), 7.50 (t, 1
H), 7.62 (d, 1 H), 8.01 (t, 1 H), 8.58 (d, 1 H), 8.82 (d, 1 H),
8.90 (s, 1 H), 9.44 (bs, 1 H), 9.64 (bs, 1 H) MS: m/z=415.2
[M+H].sup.+.
EXAMPLE 85
Preparation of Methyl
3-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-buty- l(dimethyl)
silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-c-
hromen-6-yl]benzoate
[0436] 639
[0437] Argon was bubbled through a solution of the compound of
Example 81 (5 g, 8 mmol) in toluene (100 mL) for 10 minutes. Then,
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (460
mg, 0.56 mmol) and methyl 3-bromobenzoate (2.6 g, 12 mmol) were
added in a single portion. The resulting reaction mixture was
degassed with argon for an additional 5 minutes before aqueous
Na.sub.2CO.sub.3 (2M, 40 mL, 80 mmol) was added and the solution
was heated at 85.degree. C. overnight. The product mixture was
allowed to cool to room temperature, water was added and the
biphasic mixture was extracted with ethyl acetate. The combined
organic extracts were dried over anhydrous sodium sulfate,
concentrated and purified with a Biotage column, gradient 10-30%
ethyl acetate/hexanes to obtain 3.83 g (77%) of the title compound.
MH+=633.5
EXAMPLE 86
Preparation of
3-[(2R)-2-({(tert-Butoxycarbonyl)[(2R)-2-{[tert-butyl(dimet-
hyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-
-yl]benzoic Acid
[0438] 640
[0439] The product from Example 85 (3.0 g, 4.8 mmol) was diluted
with 10 mL each of tetrahydrofuran, water, and methanol; 15 mL of 1
N sodium hydroxide (14.4 mmol) was added; and allowed solution to
stir overnight at room temperature. The solution was concentrated,
water added, and neutralized with 1 N phosphoric acid. The aqueous
layer was extracted with methylene chloride, dried over anhydrous
sodium sulfate, and concentrated in vacuo. Purified by Biotage in
gradient 10-30% ethyl acetate/hexanes, then flushed column with
ethyl acetate to 5% methanol/ethyl acetate. Yielded 2.3 g (78%) of
product. MH+=619.6
EXAMPLE 87
Preparation of
N-{3-[(2R)-2-({[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}m-
ethyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}methanesulfonamide
[0440] 641
[0441] The product of Example 86 (100 mg, 0.16 mmol),
1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide (36 mg, 0.19 mmol),
dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17
mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and
stirred overnight at room temperature. The mixture was treated with
0.5 mL 4 M HCl in 1,4-dioxane was added, the solution stirred for
0.5 hours, concentrated to dryness and the residue was purified by
preparative HPLC to obtain the title compound (47 mg, 62%). .sup.1H
NMR (CD.sub.3CN-d.sub.3) .delta. 8.91 (s, 1 H), 8.76 (d, 1 H), 8.51
(d, 1 H), 8.07 (s, 1 H), 7.97 (t, 1 H), 7.88-7.83 (m, 2 H),
7.62-7.56 (m, 1 H), 7.50-7.47 (m, 2 H), 6.98 (d, 1 H), 5.46 (d, 1
H), 4.54-4.47 (m, 1 H), 3.52 (dd, 2 H), 3.37 (s, 3 H), 3.39-3.25
(m, 2 H), 2.99-2.90 (m, 2 H), 2.14-2.09 (m, 1 H), 1.86-1.79 (m, 1
H). MH+=482.2
EXAMPLE 88
[0442] Method A. Preparation of
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl-
)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic
Acid 642
[0443] Argon was bubbled through a solution of Example 81 (100 mg,
0.16 mmol) in toluene (2 mL) for 10 minutes. Then, palladium
acetate (2 mg, 0.008 mmol), 2-(di-tert-butylphosphino)biphenyl (5
mg, 0.016 mmol), and methyl 4-bromo-3-methylbenzoate (55 mg, 0.24
mmol) were added in a single portion. The resulting reaction
mixture was degassed with argon for an additional 5 minutes before
aqueous Na.sub.2CO.sub.3 (2M, 1 mL, 1.68 mmol) was added and the
solution was heated at 85.degree. C. overnight. The product mixture
was allowed to cool to room temperature, water was added, and the
biphasic mixture was extracted with ethyl acetate. 1 mL of 4 M
HCl/dioxane was added to the combined organic extracts, stirred for
0.5 hour, and concentrated in vacuo. Then, 1 mL of 1 N sodium
hydroxide was added, stirred for 0.5 hour, filtered, and purified
by preparative HPLC to obtain 8 (7 mg, 11%). MH.sup.+=419.3
[0444] Method B. Preparation of
4-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl-
)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic
Acid 643
[0445] Using the same procedure described in Method A with
(1R)-1-(3-pyridinyl)-2-({[(2S)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol (Example 81,
Method B), the title compound was obtained in 38% yield: .sup.1H
NMR (CD.sub.3OD) .delta. 7.08 (d, J=2.3 Hz, 1 H), 6.95 (dd, J=5.1,
1.8 Hz, 1 H), 6.41-6.37 (m, 1 H), 6.30-6.28 (m, 1 H), 6.24-6.21 (m,
1 H), 5.94-5.89 (m, 1 H), 5.60 (d, J=8.0 Hz, 1 H), 5.50-5.47 (m, 2
H), 5.33 (d, J=8.8 Hz, 1 H), 3.52 (dd, J=9.6, 3.6 Hz, 1 H),
3.38-3.33 (m, 1 H), 2.84-2.78 (m, 1 H), 1.78 (s, 3 H), 1.75-1.72
(m, 1 H), 1.68-1.60 (m, 1 H), 1.43-1.33 (m, 1 H), 1.31-1.25 (m, 1
H), 0.58-0.52 (m, 1 H), 0.32-0.23 (m, 1 H). LC-MS m/z 419.2
(MH.sup.+).
[0446] Method C. Preparation of
4-[(2S)-2-({[2-hydroxy-2-(3-pyridinyl)ethy-
l]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic Acid
644
[0447] Starting with the
(2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7,
Method B) and racemic 2-amino-1-(3-pyridinyl)ethanol
dihydrochloride, and using the procedures described in Examples
35-38 and Method A above, the title compound was prepared. LC-MS
m/z 419.2 (MH.sup.+), RT=1.45 minutes.
[0448] Using the procedures outlined in Examples 69-88 and using
the appropriate aryl halides, trifluoromethanesulfonates,
sulfonamides and/or benzoates, the following compounds were
prepared and characterized.
5TABLE 5 645 Calculated MS RT (minutes) Example R' Y MW [M +
H.sup.+] LC-MS 89 646 647 481 482.2 1.33 90 648 649 557 558.2 2.05
91 650 651 557 558.31 2.01 92 652 653 573 574.2 1.98 93 654 655 561
562.2 2 94 656 657 577 578.2 2.15 95 658 659 591 592.2 2.25 96 660
661 644 645.2 2.24 97 662 663 509 510.2 1.76 98 664 665 509 510
1.75 99 666 667 481 482.2 1.14 100 668 669 543 544.2 1.88 101 670
671 573 574.2 1.86 102 672 673 561 562.2 1.89 103 674 675 557 558.3
1.96 104 676 677 557 558.2 1.9 105 678 679 577 578.2 2.02 106 680
681 584 583,585 2.01 107 682 683 509 510 0.39 108 684 685 495 496
0.17 109 686 687 596 595,597 1.68 110 688 689 616 617 1.89 111 690
691 636 637 1.16 112 692 693 558 559 0.47 113 694 695 549 550 1.79
114 696 697 509 510 2.04 115 698 699 523 524 2.12 116 700 701 535
536 0.8 117 702 703 507 508 1.9 118 704 705 562 563 3.4
[0449]
6TABLE 6 706 HPLC Example MS RT No Y [M + H].sup.+ (min) 119 707
419.3 1.61 120 708 465.1 1.37 121 709 433 1.42 122 710 457 1.68 123
711 462 1.56 124 712 439 1.1 125 713 435 0.92 126 714 477.2 127 715
537.3 2.30 128 716 487.4 2.21 129 717 479.2 1.74 130 718 463.2 1.86
131 719 463.1 1.88 132 720 475.2 1.95 133 721 477.2 2.08 134 722
491.2 2.17 135 723 435.2 1.66 136 724 449.2 1.87 137 725 464.2 1.91
138 726 450.2 1.59 139 727 419.5 1.68 140 728 405.2 1.68 141 729
419.2 1.91 142 730 406.2 0.79 143 731 458.2 1.95 144 732 479.3 1.55
145 733 465.3 1.13 146 734 420.2 1.15 147 735 495.3 1.63 148 736
405.2 1.53 149 737 419.2 1.55 150 738 423.2 1.26 151 739 406.2 0.62
152 740 419.3 1.58 153 741 419.2 1.69 154 742 411.1 1.18 155 743
433.3 1.94 156 744 411.3 1.52 157 745 411.3 1.33 158 746 406.3 0.62
159 747 395.2 1.07 160 748 455.3 1.99 161 749 451.3 1.17 162 750
423.3 0.63 163 751 500.6 2.27 164 752 472.4 1.99 165 753 516.5 2.38
166 754 488.3 1.96
EXAMPLE 167
Preparation of methyl
4-[((2R)-2-{[(tert-butoxycarbonyl)((2R)-2-(3-pyridin-
yl)-2-{[(1,1,2,2-tetramethylpropyl)-silyl]oxy}ethyl)amino]methyl}-3,4-dihy-
dro-2H-chromen-6-yl)methyl]benzoate
[0450] 755
[0451] A solution of 100 mg (0.16 mmol) of
(1R)-1-(3-pyridinyl)-2-({[(2R)--
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-y-
l]methyl}amino)ethanol Example 81) dissolved in 5 mL of toluene and
1 mL 1,4-dioxane, was bubbled under argon for 10 minutes. Then, 10
mg (0.0122 mmol) of Pd(dppf)Cl.sub.2 complex with methylene
chloride (1:1) and 54.98 mg (0.24 mmol) of methyl
4-(bromomethyl)benzoate (Aldrich Chemical Co.) were added, and the
mixture was bubbled under argon for another 5 minutes. Finally, 1.0
mL (2.0 mmol) of 2M aqueous sodium carbonate was added, and the
mixture was stirred under argon at 85.degree. C. for 16 hours.
After this time, the mixture was allowed to cool to ambient
temperature, filtered through Celite.RTM., rinsed with ethyl ether,
and concentrated in vacuo. The product was purified by flash
chromatography using 30% ethyl acetate/hexanes as the eluant to
provide 77.2 mg of product; MH+ 647.4.
EXAMPLE 168
Preparation of
4-{[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino.qua-
drature.methyl)-3,4-dihydro-2H-chromen-6-yl]methyl}benzoic Acid
[0452] 756
[0453] To a solution of 77.2 mg (0.11 mmol) methyl
4-[((2R)-2-{[(tert-buto-
xycarbonyl)((2R)-2-(3-pyridinyl)-2-{[(1,1,2,2-tetramethylpropyl)silyl]oxy}-
ethyl)amino]-methyl}-3,4-dihydro-2H-chromen-6-yl)methyl]benzoate
(Example 167) in 1 mL of tetrahydrofuran was added 0.54 mL of 1M
LiOH and 0.27 mL methanol. The mixture was stirred at room
temperature for 3 hours after which point 0.5 mL of 1N phosphoric
acid was added to the solution. The mixture was partitioned between
ethyl acetate (3.times.5 mL) and water (5 mL). The organic layer
was washed with saturated sodium chloride, dried over sodium
sulfate, filtered, and concentrated. To the residue was added 0.4
mL of hydrochloric acid in dioxane. This solution was stirred at
room temperature for 0.5 hour. The solution was then washed with
water and concentrated in vacuo, followed by purification by
preparative HPLC (gradient of 100:0 0.1% TFA/H.sub.20:acetonitrile
to 30:70 0.1% TFA/H.sub.20:acetonitrile) to obtain 16.4 mg of
product as the TFA salt. MH+ 419.3. .sup.1H NMR (DMSO d.sub.6,
.delta.): 8.89 (br. s, 1 H), 8.63 (s, 1 H), 8.57 (d, 1 H), 7.88
(dt, 1 H), 7.85 (s, 1 H), 7.82 (s, 1 H), 7.50 (dd, 1 H), 7.32 (s, 1
H), 7.29 (s, 1 H), 6.96 (m, 2 H), 6.73 (d, 1 H), 6.38 (br. s, 1 H),
5.08 (m, 1 H), 4.38 (m, 1 H), 2.76 (m, 1 H), 2.71 (m, 1 H), 1.99
(m, 1 H), 1.67 (m, 1 H).
EXAMPLE 169
Preparation of
(2R)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-6-nitro-3,4-di-
hydro-2H-chromene-2-carboxamide
[0454] 757
[0455] (2R)-6-Nitro-3,4-dihydro-2H-chromene-2-carboxylic acid (4.1
g, 18 mmol) and (1R)-2-amino-1-(3-pyridinyl)ethanol (5.0 g, 24
mmol) (both described in U.S. Pat. No. 6,051,586) were suspended in
CH.sub.2Cl.sub.2 and stirred vigorously. Triethylamine (9.2 mL, 66
mmol) was added followed by hydroxybenzotriazole (4.9 g, 36 mmol)
and EDCl (6.9 g, 36 mmol), and the reaction was stirred overnight.
After 18 hours, TLC showed no remaining acid starting material, so
the reaction was partitioned between water and CH.sub.2Cl.sub.2 and
the organic layer was washed 3.times.100 mL of water. The organic
layer was washed with 1N HCl, which removed the product into the
aqueous layer. This aqueous layer was washed with CH.sub.2Cl.sub.2
and the organic was discarded. The aqueous solution was then
basified and became cloudy with a white precipitate. The basified
mixture was extracted with 3.times.100 mL of CH.sub.2C.sub.2.
[0456] The combined organic layer was concentrated, affording the
product (4.5 g) as a light yellow foam. .sup.1H NMR (DMSO-d.sub.6,
.delta.): 8.4 (d, 2H), 8.1 (t, 1H), 8.0 (m, 2H), 7.6 (d, 1H), 7.3
(m, 1H), 7.0 (d, 1H), 5.6 (s, 1H), 4.7 (m, 2H), 3.3 (m, 2H) 2.8 (m,
1H), 2.6 (m, 1H), 2.2 (m, 1H), 1.9 (m, 1H); LC/MS: m/z 343,
MH.sup.+344.
EXAMPLE 170
Preparation of (1
R)-2-({[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}- amino)-
1-(3-pyridinyl)ethanol
[0457] 758
[0458]
(2R)-N-[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]-6-nitro-3,4-dihydro-2H-
-chromene-2-carboxamide (Example 169, 1.0 g, 3 mmol) was dissolved
in 15 mL of THF and borane-dimethylsulfide complex (1.4 mL, 12.6
mmol) was added dropwise. The reaction was refluxed for one hour
after which TLC showed no remaining starting material. Methanol
(0.5 mL) was then added dropwise followed by 6N HCl (0.5 mL) and
the reaction was refluxed an additional 1.5 hours. The solution was
then cooled and diluted with water and ethyl acetate, and adjusted
to about pH 9 with 1N NaOH. The organic layer was dried and
evaporated to afford the product (650 mg) as a yellow solid.
.sup.1H NMR (DMSO-d.sub.6, .delta.): 8.6 (s, 1H), .delta. 8.5 (d,
1H), .delta. 8.1 (s, 1H), .delta. 8.0 (d, 1H), .delta. 7.8 (d, 1H),
.delta. 7.4 (m, 1H), .delta. 7.0 (d, 1H), .delta. 5.6 (s, 1 H),
.delta.4.8 (m, 1H), .delta. 4.3 (m, 1H), .delta. 3.2 (s, 1H),
.delta. 2.9 (m, 2H), .delta. 2.8 (m, 2H), .delta. 2.1 (m, 1H),
.delta. 1.8 (m, 1H); LC/MS: m/z 329, MH.sup.+330
EXAMPLE 171
Preparation of tert-butyl
(2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-nitr-
o-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
[0459] 759
[0460] (1
R)-2-({[(2R)-6-nitro-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-
-(3-pyridinyl)ethanol (Example 170, 650 mg, 2 mmol) was dissolved
in 12 mL THF, di-tert-butyl-dicarbonate (440 mg, 2 mmol) was added,
and the reaction was stirred and monitored by TLC. Upon completion,
when the disappearance of starting material was observed, the
reaction was partitioned between water and ethyl acetate. The crude
product obtained by concentration of the organic layer was purified
by filtration through a silica plug to give 777 mg of material as a
white foam. .sup.1H NMR (DMSO-d.sub.6, .delta.): 8.4 (m, 2H), 8.1
(s, 1H), 7.9 (d, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 6.9 (d, 1H), 5.6
(d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 3.5 (m, 4H), 2.8 (m, 2H), 2.0
(m, 1H), 1.6 (m, 1H), 1.2 (s, 9H); LC/MS: m/z 429, MH.sup.+430.
EXAMPLE 172
Preparation of tert-butyl
[(2R)-6-amino-3,4-dihydro-2H-chromen-2-yl]methyl-
[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate
[0461] 760
[0462] tert-Butyl
(2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-nitro-3,4-di-
hydro-2H-chromen-2-yl]methyl}carbamate (Example 171, 500 mg, 1.2
mmol) was dissolved in degassed THF, and to the solution was added
Pd/C (50 mg, 10%) under argon and cooled to 0.degree. C. NaBH.sub.4
was dissolved in ethanol and added to the reaction slowly to avoid
excessive bubbling. After gas evolution had stopped, the reaction
was warmed to room temperature and monitored by TLC. When complete,
the reaction was cooled to 0.degree. C. and quenched by the
addition of ice. The black precipitate was then filtered through
Celite.RTM. and the filtrate was concentrated in vacuo until
cloudy. The filtrate was then extracted with ethyl acetate and the
crude material was purified via flash chromatography to yield the
product (30%). .sup.1H NMR (DMSO-d.sub.6, .delta.): 8.4 (m, 2H),
7.7 (m, 1 H), 7.4 (m, 1H), 6.4 (d, 1H), 6.3 (s, 1H), 6.2 (d, 1H),
5.6 (d, 1H), 4.8 (m, 1H), 4.5 (m, 1H), 3.5 (m, 2H), 3.4 (m, 2H),
2.8 (m, 2H), 1.8 (m, 1H), 1.5 (m, 1H), 1.2 (d, 9H); LC/MS: m/z 399,
MH.sup.+ 400
EXAMPLE 173
Preparation of
3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyri-
dinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic
acid
[0463] 761
[0464] Utilizing a procedure reported by Schutze (EP 0067352 B2), a
solution of 510 mg (1.25 mmol) of Example 172 in 15 mL of acetone
was cooled to 0.degree. C., and 1.3 mL (2.5 mmol) of 2N
hydrochloric acid was added. Sodium nitrite (95 mg, 1.38 mmol)
dissolved in 1.3 mL of water at 0.degree. C. was added slowly to
the reaction flask.
[0465] The resulting mixture was then allowed to stir at 0.degree.
C. for 1 hour while 270 mg (1.75 mmol) 3-mercaptobenzoic acid, 279
mg (1.75 mmol) copper sulfate, and 1.24 mL water were mixed
together at room temperature for 0.5 hour. After this time, the
cold (0.degree. C.) solution was added slowly to the room
temperature solution. The resulting mixture was stirred at room
temperature for 16 hours. The reaction mixture was then added to
100 mL water and extracted 3 times with 25 mL ethyl acetate. The
combined organic phases were washed with water and brine, and dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The crude product was used without further purification.
EXAMPLE 174
Preparation of
3-{[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}met-
hyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benzoic acid
[0466] 762
[0467] To 670 mg (1.25 mmol) of crude
3-{[(2R)-2-({(tert-butoxycarbonyl)[(-
2R)-2-hydroxy-2-(3-pyridinyl)ethyl]aminomethyl)-3,4-dihydro-2H-chromen-6-y-
l]sulfanyl}benzoic acid (Example 173) diluted in 5 mL 1,4-dioxane,
was added 0.5 mL of 6N hydrochloric acid slowly. The resulting
mixture was stirred at 45.degree. C. for 2 hours. After this time
the mixture was concentrated in vacuo, dissolved in 2 mL of 1:1
methanol to water, and purified by HPLC (0-70% acetonitrile/0.1%
TFA) to afford 28.5 mg (5% yield) of the desired product as the bis
TFA salt. MH+437.3. .sup.1H NMR (CDCl.sub.3, .delta.): 8.91 (br. S,
1 H), 8.63 (d, 1 H), 8.56 (dd, 1 H), 7.89 (m, 1 H), 7.72 (dt, 1 H),
7.62 (m, 1 H), 7.49 (m, 1 H), 7.39 (m, 1 H), 7.31 (m, 1 H), 7.27
(m, 1 H), 7.24 (dd, 1 H), 6.90 (d, 1 H), 6.35 (br. S, 1 H), 5.07
(m, 1 H), 4.48 (m, 1 H), 3.32 (m, 4 H), 3.16 (m, 1 H), 2.78 (m, 2
H), 2.04 (m, 1 H), 1.71 (m, 1 H).
EXAMPLE 175
Preparation of methyl
3-[{(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2--
(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfanyl}benz-
oate
[0468] 763
[0469] To 650 mg (1.25 mmol) of
3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2--
hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sul-
fanyl}benzoic acid (Example 173) dissolved in 10 mL 1:1
methanol/ethyl acetate, was added 3 mL of 2M trimethylsilyl
diazomethane dropwise. The resulting solution was then allowed to
stir at room temperature for 16 hours. The solution was then
diluted with ethyl acetate, washed with water and brine, and
concentrated in vacuo. The crude mixture was purified by Biotage
with 75% ethyl acetate/hexanes to obtain 223 mg (33% yield) of
product; MH+ 551.2.
EXAMPLE 176
Preparation of methyl 3-{[(2
R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-
-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfonyl}ben-
zoate
[0470] 764
[0471] A solution of 0.5 mL (3.6 mmol) of trifluoroacetic anhydride
in 2 mL methylene chloride was cooled to 0.degree. C., and then
0.11 mL (1.1 mmol) of 30% hydrogen peroxide was added to the
solution slowly, allowing the solution to stir at this temperature
for 5 minutes. Then a solution of 200 mg (0.36 mmol) methyl
3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hy-
droxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfa-
nyl}benzoate (Example 175) in 1 mL of methylene chloride was added
to the cold solution dropwise and the reaction mixture was stirred
at 0.degree. C. for 1 hour, followed by stirring at room
temperature for 0.5 hour. The mixture was diluted with 10 mL ethyl
ether and washed with 20 mL of 1N aqueous sodium hydroxide. The
aqueous layer was extracted with ethyl ether, and the organic phase
was washed sequentially with 20% aqueous sodium sulfite, water and
brine, dried over sodium sulfate, filtered, and concentrated in
vacuo to obtain 66.3 mg (21% yield) of crude product; MH+
583.2.
EXAMPLE 177
Preparation of
3-{[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}met-
hyl)-3,4-dihydro-2H-chromen-6-yl]sulfonyl}benzoic acid
[0472] 765
[0473] To a solution of 66.3 mg (0.11 mmol) methyl
3-{[(2R)-2-({(tert-buto-
xycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro--
2H-chromen-6-yl]sulfonyl}benzoate (Example 176) diluted in 5 mL
1,4-dioxane, was slowly added 0.05 mL of 6N hydrochloric acid. The
resulting mixture was then stirred at 45.degree. C. for 2 hours.
The crude mixture was concentrated in vacuo, then purified by
preparative HPLC. The purified intermediate product was then
treated with 0.8 mL of 2N sodium hydroxide and allowed to stir for
36 hours and then concentrated in vacuo. The crude product was then
purified by preparative HPLC (0-70% Acetonitrile/0.1% aq TFA) to
obtain 6.5 mg of product as the bis-TFA salt. MH+ 469.3 (free
base)
EXAMPLE 178
Preparation of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl
trifluoromethanesulfonate
[0474] 766
[0475] To 2,4-dihydroxybenzoic acid (Aldrich) (10.0 g, 64.9 mmol,
1.0 eq.) was added trifluoroacetic acid (80 mL), trifluoroacetic
anhydride (50 mL), and acetone (10 mL) at 0.degree. C. The reaction
mixture was allowed to warm up slowly to room temperature and
stirred for 48 hours. The mixture was then concentrated under
reduced pressure. The resulting residue was washed with saturated
sodium bicarbonate (100 mL), extracted with ethyl acetate
(3.times.100 mL). The combined extracts were dried over magnesium
sulfate, filtered, and concentrated under reduced pressure to give
crude product 9.2 g as yellow solid.
[0476] The crude product was treated with trifluoromethanesulfonic
anhydride (8.8 mL, 52.11 mmol, 1.1 eq.) in the presence of pyridine
(50 mL) at 0.degree. C. for 8 hours. The resulting mixture was then
diluted with distilled water (100 mL), extracted with ethyl acetate
(3.times.50 mL), and washed with saturated sodium bicarbonate (60
mL) and brine (100 mL). The combined extracts were dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure to give brown oil. Purification by flash chromatography on
a silica gel column (20%-40% ethyl acetate/hexanes) yielded the
desired product as a white solid (8.3 g, 40%). .sup.1H NMR
(CDCl.sub.3) .delta. 8.08 (d, 1H), 7.03 (d, 1H), 6.94 (s, 1H), 1.77
(s, 6H), GC-MS: 326 (M.sup.+), retention time: 7.557 min.
EXAMPLE 179
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyr-
idinyl)ethyl{[(2S)-6-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-3,4-dihy-
dro-2H-chromen-2-yl]methyl}carbamate
[0477] 767
[0478] By using procedure described in Example 85, the compounds of
Example 178 and Example 81 were coupled to provide the desired
compound. LC-MS: 421.4 (MH.sup.+-Boc), retention time: 1.54
min.
EXAMPLE 180
Preparation of
2-hydroxy-4-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]-
amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid
[0479] 768
[0480] To a solution of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}- -2-(3-pyridinyl)
ethyl{[(2S)-6-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl-
)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 179, 0.07
g, 0.104 mmol, 1.0 eq.) in tetrahydrofuran (3 mL) was added 4N
hydrochloric acid in 1,4-dioxane (2 mL) at room temperature. The
reaction mixture was allowed to stir at room temperature for 16
hours. The mixture was then concentrated under reduced pressure.
Purification by HPLC afforded the desired HCl salt as a white solid
(0.005 g, 10%). LC-MS: 421.4 (MH.sup.+), retention time: 1.54
min.
EXAMPLE 181
Preparation of methyl
4-[(2S)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-buty- l(dimethyl)
silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-c-
hromen-6-yl]-2-hydroxybenzoate
[0481] 769
[0482] To a solution of the compound of Example 179 in methanol (10
mL) was added potassium carbonate (0.12 g) at room temperature. The
reaction mixture was allowed to stir at room temperature for 18
hours and then concentrated under reduced pressure. The resulting
residue was washed with distilled water (10 mL) and extracted with
ethyl acetate (3.times.10 mL). The combined extracts were dried
over magnesium sulfate, filtered and concentrated under reduced
pressure to afford the desired product as pale yellow oil (0.68 g,
94%). LC-MS: 649.8 (MH.sup.+), retention time: 3.80 min.
EXAMPLE 182
Preparation of methyl
4-[(2S)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-buty- l(dimethyl)
silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-c-
hromen-6-yl]2-isobutoxybenzoate
[0483] 770
[0484] To a solution of the compound of Example 181 (0.097 g,
0.0015 mmol, 1.0 eq.) in N,N-dimethylformamide (0.5 mL) were added
1-iodo-2-methylpropane (0.10 ml) and potassium carbonate (0.10 g).
The reaction mixture was stirred at 60.degree. C. for 16 hours. The
mixture was diluted with distilled water (2 mL) and extracted with
ethyl acetate (3.times.2 mL). The combined extracts were dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to give the crude as clear oil (0.076 g, 74%). LC-MS: 705.3
(MH.sup.+), retention time: 4.01 min.
EXAMPLE 183
Preparation of
4-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid
[0485] 771
[0486] To a solution of the compound of Example 182 (0.076 g, 0.11
mmol, 1.0 eq.) in methanol (1.0 mL) was added 1M lithium hydroxide
(1.0 mL). The reaction mixture was stirred at room temperature for
16 hours. The mixture was neutralized by 1N hydrochloric acid and
then extracted with ethyl acetate (3.times.2 mL). The extracts were
concentrated under reduced pressure to give white solid. To this
crude was added 4N hydrochloric acid in 1,4-dioxane (1.5 mL) and
the mixture was stirred for 3 hours at room temperature. The
resulting mixture was concentrated under reduced pressure to give
white solid. Purification by HPLC yielded the desired HCl salt as a
white solid (15.7 mg, 26%). LC-MS: 477.2 (MH.sup.+), retention
time: 1.97 min.
[0487] By using procedure described in Examples 182 and 183, the
following analogs were prepared.
7TABLE 7 772 Calcu- RT lated MS (minutes) Example R' MW [M +
H.sup.+] LC-MS 184 773 434 435.1 1.45 185 774 448 449.1 1.73 186
775 462 463.2 1.87 187 776 478 479.2 1.63 188 777 462 463.2
1.83
EXAMPLE 189
Preparation of phenylmethyl 4-bromo-2-fluorobenzoate
[0488] 778
[0489] Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to
a solution of 4-bromo-2-fluorobenzoic acid. (1.0 g, 4.6 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (1.36 ml, 9.2 mmol, 2.0 eq.) in
anhydrous acetonitrile (20 mL). The reaction was stirred at room
temperature for 18 hours before removing the solvent in vacuo. The
residue was diluted with ether and washed with water, saturated
aqueous sodium bicarbonate, saturated aqueous ammonium chloride,
and brine. The organic layer was dried (MgSO.sub.4) and
concentrated in vacuo to provide the title compound as a pale
yellow oil that crystallized into long needles upon standing (1.4
g, 99%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.82 (t, 1H),
7.42-7.31 (m, 7 H), 5.35 (s, 2 H); GC/MS m/z 308/310 (M.sup.+ and
M.sup.+2).
EXAMPLE 190
Preparation of phenylmethyl 4-bromo-2-(phenyloxy)benzoate
[0490] 779
[0491] Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg,
0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.)
and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in
anhydrous N,N-dimethylformamide and was heated at 85.degree. C. for
5 hours. The mixture was cooled and partitioned between diethyl
ether and water. The aqueous layer was separated and extracted with
fresh ether. The organic layers were combined, washed with brine
(4.times.), dried (MgSO.sub.4), and concentrated in vacuo to a
crude oil. The crude was purified by flash chromatography on silica
gel eluted with 95:5 hexanes/ether to provide the title compound as
a colorless oil that crystallized upon standing (110 mg, 34%):
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.84 (d, 1 H), 7.39-7.27
(m, 7 H), 7.17-7.10 (m, 1 H), 6.98-6.91 (m, 2 H), 6.85 (d, 2 H),
5.30 (s, 2 H); R.sub.f0.51 (4:1 hexanes/diethyl ether).
EXAMPLE 191
Preparation of phenylmethyl
4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)
(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]}[(1,1-dimethylethyl)oxy]carbon-
yl}amino)
methyl]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate
[0492] 780
[0493] Argon gas was bubbled through a solution of the compound of
Example 81 (160 mg, 0.25 mmol) in toluene (5 mL), dioxane (1 mL),
and aqueous Na.sub.2CO.sub.3 (0.5 mL of a 2.0 M solution) for 10
minutes. Pd(dppf)Cl.sub.2(20 mg, 0.025 mmol, 0.1 eq.) and
phenylmethyl 4-bromo-2-(phenyloxy)benzoate (Example 190, 110 mg,
0.27 mmol, 1.1 eq.) were added, and argon was bubbled through the
mixture for an additional 5 minutes before being stirred vigorously
at 85.degree. C. for 3 hours. The reaction mixture was cooled and
filtered through a pad of Celite.RTM. with the aid of ethyl
acetate. The filtrate was transferred to a separatory funnel where
the water layer was removed. The organic layer was dried
(MgSO.sub.4) and concentrated in vacuo to a crude oil. The crude
was purified by flash chromatography on silica gel eluted on a
gradient from 100:0 to 70:30 hexanes/ethyl acetate to provide the
title compound as a colorless oil (69 mg, 34%): .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.58-8.47 (m, 2 H), 7.96 (d, 1 H), 7.64
(dd, 1 H), 7.32 (d, 1 H), 7.27-7.20 (m, 10 H), 7.17-7.12 (m, 1 H),
7.00 (t, 1 H), 6.89 (d, 2 H), 6.72 (d, 1 H), 5.20 (s, 2 H),
5.11-4.90 (m, 1 H), 4.21-4.03 (m, 1 H), 3.73 (d, 1 H), 3.63-3.54
(m, 1 H), 3.42-3.14 (m, 2 H), 2.81-2.70 (m, 2 H), 1.98-1.89 (m, 1
H), 1.68-1.60 (m, 1 H), 1.42 (s, 9 H), 0.83 (s, 9 H), -0.01 (s, 3
H), -0.018 (s, 3 H); MS m/z 801.2 (MH.sup.+).
EXAMPLE 192
Preparation of
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}meth-
yl)-3,4-dihydro-2H-chromen-6-yl]-2-(phenyloxy)benzoic acid
[0494] 781
[0495] Phenylmethyl
4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)sil-
yl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methy-
l]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate (Example 191,
69 mg, 0.086 mmol) was stirred over a suspension of 10% Pd/C (7 mg)
in ethanol (5 mL) under a hydrogen atmosphere for 15 hours. Solids
were removed by filtration through Celite.RTM., and the filtrate
was concentrated in vacuo. The carboxylic acid intermediate was
collected as a colorless oil (25 mg, 41%): .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.66-8.58 (m, 2 H), 7.99 (d, 1 H), 7.92 (d, 1
H),7.58-7.54 (m, 2 H), 7.51-7.41 (m, 2 H), 7.37-7.34 (m, 2 H),
7.21-7.16 (m, 2 H), 7.10 (d, 2 H), 6.86 (d, 1 H), 5.27-5.15 (m, 1
H), 4.38-4.31 (m, 1 H), 3.86-3.54 (m, 4 H), 2.96-2.90 (m, 2 H),
2.13-2.00 (m, 1 H), 1.87-1.75 (m, 1 H), 1.56 (d, 9 H), 1.00 (s, 9
H), 0.18 (d, 3 H), 0.00 (s, 3 H). The carboxylic acid intermediate
(25 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at
room temperature for 18 hours. The volatile components were removed
by rotary evaporation, and the residue was washed with
dichloromethane. After drying under vacuum, the title compound was
collected as the di-hydrochloride salt (16 mg, 80%): .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 9.04 (broad s, 1 H), 8.89 (broad s, 1
H), 8.77 (d, 1 H), 8.15 (t, 1 H), 8.00 (d, 1 H), 7.46 (d, 1 H),
7.38-7.33 (m, 4 H), 7.14-7.08 (m, 2 H), 6.98 (d, 3 H), 5.45 (d, 1
H), 4.50 (t, 1 H), 3.76-3.55 (m, 5 H), 3.52-3.35 (m, 2 H),
2.99-2.85 (m, 2 H), 2.18-2.11 (m, 1 H), 1.85-1.75 (m, 1 H); MS m/z
497.2 (MH.sup.+ of the free base).
[0496] By employing the methods described above for Examples
190-192, the following were similarly prepared and
characterized:
8TABLE 8 782 Example Calculated MS LC-MS No. R" MW [M + H+] RT
(min) 193 --F 514.19 515.1 1.88 194 --Cl 530.16 531.2 2.01 195
--CH.sub.3 510.22 511.2 1.96 196 --OCH.sub.3 526.21 527.2 1.94 197
--CO.sub.2Et 568.22 569.2 1.99 198 --SO.sub.2CH.sub.3 574.18 575.1
1.77
EXAMPLE 199
Preparation of tert-butyl
benzyl{[(2S)-6-bromo-3,4-dihydro-2H-chromen-2-yl-
]methyl}carbamate
[0497] 783
[0498] To a solution of
N-benzyl[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl] methanamine
(Example 217, 20.0 g, 60.2 mmol, 1.0 mmol) in tetrahydrofuran (200
mL) was added di-tert-butyl dicarbonate (14.45 g, 66.22 mmol, 1.1
eq.) at room temperature. The reaction mixture was stirred at room
temperature for 18 hours and then quenched with distilled water
(100 mL). The resulting mixture was extracted with ethyl acetate
(3.times.50 mL) and washed with saturated sodium bicarbonate (50
mL) and brine (80 mL). The combined extracts were dried over
magnesium sulfate, filtered through silica gel, and concentrated
under reduced pressure to yield the desired product as colorless
oil which was used without further purification (25 g, 100%).
EXAMPLE 200
Preparation of tert-butyl
benzyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxab-
orolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
[0499] 784
[0500] To a degassed solution of the compound of Example 199 (15.0
g, 57.24 mmol, 1.0 mmol) in dimethyl sulfoxide (120 mL) was added
bis(pinacolato)diboron (15.0 g, 57.24 mmol, 1.0 eq.),
dichloro[1,1'-bis(diphenylphospphino)ferrocene]palladium(II)
dichloromethane adduct (1.46 g, 1.72 mmol, 0.03 eq.) and potassium
acetate (17.0 g, 171.72 mmol, 3.0 eq.) under argon atmosphere at
room temperature. The reaction mixture was allowed to heat up at
85.degree. C. under argon atmosphere for 24 hours. The mixture was
then allowed to cool down to room temperature and filter through
silica gel. The filtrates were extracted with diethyl ether
(3.times.100 mL). The combined extracts were washed with saturated
sodium bicarbonate (50 mL) and brine (80 mL), dried over magnesium
sulfate, filtered through silica gel, and concentrated under
reduced pressure to yield yellow oil. Purification by flash
chromatography on a silica gel column (5%-10% ethyl
acetate/hexanes) yielded the desired product as yellow oil (13.5 g,
81%). LC-MS: 479.9 (MH.sup.+), retention time: 4.41 min.
EXAMPLE 201
Preparation of tert-butyl
benzyl{[(2R)-6-(2,2-dimethyl-4-oxo-4H-1,3-benzod-
ioxin-7-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
[0501] 785
[0502] By using the procedure described in Example 85, the
compounds of Example 200 and Example 178 were coupled to provide
the desired compound. LC-MS: 529.9 (MH.sup.+), retention time: 4.36
min.
EXAMPLE 202
Preparation of methyl
4-((2R)-2-{[benzyl(tert-butoxycarbonyl)amino]methyl}-
-3,4-dihydro-2H-chromen-6-yl)-2-hydroxybenzoate
[0503] 786
[0504] By using the procedure described in Example 181, the title
compound was prepared. LC-MS: 503.7 (MH.sup.+), retention time:
4.51 min.
EXAMPLE 203
Preparation of methyl
4-((2R)-2-{[benzyl(tert-butoxycarbonyl)amino]methyl}-
-3,4-dihydro-2H-chromen-6-yl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate
[0505] 787
[0506] By using the procedure described in Example 12, the compound
of Example 202 was converted into the title compound. LC-MS: 635.6
(MH.sup.+), retention time: 4.48 min.
EXAMPLE 204
Preparation of methyl
5-{(2R)-2-[(benzylamino)methyl]-3,4-dihydro-2H-chrom-
en-6-yl}-4'-methyl-1,1'-biphenyl-2-carboxylate
[0507] 788
[0508] To a degassed solution of the compound of Example 203 (0.31
g, 0.49 mmol, 1.0 eq.) in toluene (1.0 mL) was added
4-methylphenylboronic acid (0.10 g, 0.73 mmol, 1.5 eq.),
dichloro[1,1'-bis(diphenylphosphino)ferroce- ne]palladium(II)
dichloromethane adduct (0.028 g, 0.034 mmol, 0.07 eq.) and 2M
sodium carbonate (2.4 mL, 4.88 mmol, 10.0 eq.) under argon
atmosphere at room temperature. The reaction mixture was allowed to
heat up at 80.degree. C. under argon atmosphere for 18 hours. The
mixture was diluted with distilled water (3 mL) and extracted with
diethyl ether (3.times.2 mL). The combined extracts were dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. The resulting residue was then treated with 4N
hydrochloric acid (1.0 mL) in tetrahydrofuran (3 ml) and stirred at
room temperature for 48 hours. The mixture was concentrated under
reduced pressure to give white solid. Purification by HPLC followed
yielded the desired product as clear oil (0.18 g, 77%). LC-MS:
578.0 (MH.sup.+), retention time: 4.63 min.
EXAMPLE 205
Preparation of
5-[(2R)-2-([(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methy-
l)-3,4-dihydro-2H-chromen-6-yl]-4'-methyl-1,1'-biphenyl-2-carboxylic
acid
[0509] 789
[0510] To a solution of the compound of Example 204 (0.18 g, 0.38
mmol, 1.0 eq.) in isopropanol (4.0 mL) were added the compound of
Example 1 (0.09 g, 0.57 mmol, 1.5 eq.) and potassium carbonate
(0.16 g, 1.13 mmol, 3.0 eq.) at room temperature. The reaction
mixture was allowed to heat up at 95.degree. C. for 16 hours. The
mixture was diluted with distilled water (6 mL) and extracted with
ethyl acetate (3.times.6 mL). The combined extracts were dried over
magnesium sulfate, filtered and concentrated under reduced
pressure. Purification by HPLC yielded the intermediate as a
colorless oil. The pure intermediate was then treated with 1M
lithium hydroxide (1.0 mL) in the presence of methanol (2.0 mL) and
stirred at 80.degree. C. for 15 hours. The mixture was neutralized
by 1N hydrochloric acid and then extracted with ethyl acetate
(3.times.2 mL). The extracts were concentrated under reduced
pressure to give white solid. To this crude in methanol (1 mL) was
added palladium hydroxide (0.04 g) and ammonium formate(0.045 g)
under argon atmosphere and the mixture was stirred at 65.degree. C.
for 14 hours. The resulting mixture was filtered through celite and
concentrated under reduced pressure to give white solid.
Purification by HPLC yielded the desired TFA salt as a white solid
(10 mg, 10%). LC-MS: 585.3 (MH.sup.+), retention time: 2.35
min.
EXAMPLE 206
Preparation of methyl
4-(benzyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benz- oate
[0511] 790
[0512] To a solution of methyl-4-benzyloxy-2-hydroxybenzoate (5.34
g, 21 mmol) and pyridine (2.5 g, 31.5 mmol) in dichloromethane (100
mL) was added trifluoromethanesulfonic anhydride (8.17 g, 29 mmol)
slowly. The resulting mixture was stirred overnight, washed with 1N
HCl, brine, dried, evaporated to afford 4.3 g yellow solid. (53%
yield). .sup.1HNMR Chloroform-d .delta. 4.01 (d, 3H), 5.17 (d, 2H),
6.89 (d, 1H), 7.2 (d, 1H), 7.30-7.41 (m, 5H), 8.10 (t, 1H). Rf=0.37
ethyl acetate/hexane (1/9).
Example 207
Preparation of methyl 4-(benzyloxy)-2-isobutylbenzoate
[0513] 791
[0514] To a condensed liquid 2-methyl-1-propene in THF (10 mL) at
-78.degree. C. was added 0.5 M 9-BBN (3 mL, 1.5 mmol), the mixture
was allowed to warm up to room temperature with stirring. The
mixture was transferred via a syringe to a degassed solution
containing the compound of Example 206 (0.5 g, 1.3 mmol),
Pd(dppf)Cl.sub.2 (82 mg, 0.1 mmol), K.sub.2CO.sub.3 (0.23 g, 1.7
mmol), water (2 mL) in DMF (21 mL). The resulting mixture was
heated at 60.degree. C. overnight. After removal of solvent, the
residue was purified by chromatography to afford the title compound
(0.11 g, 31% yield). .sup.1HNMR Chloroform-d .delta. 0.85 (d, 6H),
1.75-1.80 (m, 1H), 2.88 (d, 2H), 3.78 (s, 3H), 5.13 (s, 2H),
6.71-6.80 (m, 2H), 7.30-7.41 (m, 5H), 7.90 (d, 1H). Rf=0.65 ethyl
acetate/hexane (1/9).
EXAMPLE 208
Preparation of methyl 4-(hydroxy)-2-isobutylbenzoate
[0515] 792
[0516] A solution of the compound of Example 207 (0.8 g, 2.6 mmol),
10% Pd-C in MeOH (30 mL) was hydrogenated overnight. The mixture
passed through Celite.RTM. and concentrated to yellow residue (0.5
g, 89% yield). .sup.1HNMR Chloroform-d .delta. 0.90 (d, 6H),
1.82-1.90 (m, 1H), 2.89 (d, 2H), 3.90 (s, 3H), 6.73-6.80 (m, 2H),
7.88 (d, 1H). Rf=0.41 ethyl acetate/hexane (4/6).
EXAMPLE 209
Preparation of methyl
2-isobutyl-4-{[(trifluoromethyl)sulfonyl]oxy}benzoat- e
[0517] 793
[0518] To a solution of the compound of Example 198 (0.5 g, 2.4
mmol) and pyridine (0.21 g, 2.6 mmol) in dichloromethane (50 mL)
was added trifluoromethanesulfonic anhydride (0.75 g, 2.6 mmol)
slowly. The resulting mixture was stirred overnight, washed with 1N
HCl, brine, dried, evaporated to afford 0.51 g yellow solid. (64%
yield). Rf=0.63 ethyl acetate/hexane (1/9).
EXAMPLE 210
Preparation of methyl
4-{(2S)-2-[(4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-4-
-(3-pyridinyl)butyl]-3,4-dihydro-2H-chromen-6-yl}-2-isobutylbenzoate
[0519] 794
[0520] The reaction mixture of the compound of Example 81 (1.3 g,
2.1 mmol), the compound of Example 209 (0.7 g, 2.1 mmol) and
potassium carbonate (0.9 g, 6.3 mmol) in toluene (20 mL) was
flushed with Ar for 5 minutes, and Pd(PPh.sub.3).sub.4 was added
quickly to the reaction. The reaction mixture was refluxed
overnight at 45.degree. C. After removal of solvent in vacuo, the
crude product was purified by silica gel chromatography to afford
0.32 g of white solid in 23% yield. Rf=0.63 ethyl acetate/hexane
(3/7), MS: m/z (M+1) 690.43.
EXAMPLE 211
Preparation
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-
-3,4-dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid
[0521] 795
[0522] The compound of Example 210 (0.3 g, 0.4 mmol) was dissolved
in 4.0 M HCl in dioxane (30 mL) and stirred overnight. After
removal of the solvent, the residue was dissolved in MeOH-THF (1:1)
(26 mL). NaOH (0.6 g), water (3 mL) was added to the solution and
refluxed for 3 hours. After the reaction cooled to room
temperature, 2N HCl was added to pH=3. White solid was formed and
filtered to collect the white solid. The solid was purified by HPLC
to afford 0.15 g yellow solid (50% yield). .sup.1HNMR
Methanol-d.sub.4 .delta. 0.93 (d, 2H), 1.81-1.91 (m, 2H), 2.20-2.25
(m, 1H), 2.91-3.08 (m, 4H), 3.35-3.41 (m, 4H), 4.53 (t, 1H), 5.43
(d, 1H), 7.03 (d, 1H), 7.43-7.50 (m, 4H), 7.95 (d, 1H), 8.09 (t,
1H), 8.70 (d, 1H), 8.87 (s, 1H), 9.0 (s, 1H). R.sub.f=0.21
methanol/dichloromethane (2/8), MS: m/z (M+1) 461.30.
EXAMPLE 212
Preparation of methyl 4-(benzyloxy)-2-(2-phenylethyl)benzoate
[0523] 796
[0524] To a solution of styrene in THF (50 mL), 9-BBN was added
slowly, stirring at room temperature for overnight. The solution
was degassed for 5 minutes and the compound of Example 206,
Pd(dppf)Cl.sub.2, and Et.sub.3N were added at once. The reaction
mixture was heated to reflux for 3-4 hours. The solvent was
stripped. Residue was partitioned between EtOAc and H.sub.2O (100
ml/50 mL), aqueous layer was extracted with EtOAc (2.times.100 mL).
Organic solvent was dried over anhydrous Na.sub.2SO.sub.4 and
removed under the reduced pressure. The crude product was purified
by column chromatography to give 0.40 g of the desired compound
(25%). .sup.1H NMR (MeOH-d.sub.4, .delta. ppm): 8.10-8.18 (m, 2H),
10.28-10.32 (m, 2H), 3.90 (s, 3H), 7.11-7.18 (m, 2H), 7.10-7.31 (m,
10H), 8.20-8.91 (m, 2H), 8.01 (d, 1 H). Rf=0.51
(CH.sub.2Cl.sub.2:MeOH=95:5)
EXAMPLE 213
4-[(2R)-2-([{(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-
-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid
[0525] 797
[0526] Using the procedures outlined in Examples 208-211, Example
212 was converted to the title compound. MS [M+H]+ 508.2, Rf=0.24
(CH.sub.2Cl.sub.2:MeOH=95:5). H.sup.1 NMR (MeOD-d.sub.4,.delta.
ppm): 1.64 (2H, d), 1.73-1.85 (1H, m), 2.07-2.10 (1H, m), 2.90-2.96
(2H, m), 3.31 (2H, d), 3.36-3.56 (4H, m), 4.47 (1H, m), 5.38 (1H,
dd), 6.95 (1H, dd), 7.13-7.46 (9H, m), 7.87 (1H, d), 8.03-8.05 (1H,
m), 8.60 (1H, d), 8.82 (1H, br.s.), 8.95 (1H, br.s.)
EXAMPLE 214
Preparation of methyl
4-{2-[(2S)-2-({(tert-butoxycarbonyl)[(2R)-2-{[tert-b-
utyl(dimethyl)
silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2-
H-chromen-6-yl]ethyl}benzoate
[0527] 798
[0528] Using the procedure outlined in Example 212, methyl
4-vinylbenzoate was hydroborated with 9-BBN and coupled with the
compound of Example 38 to provide the title compound. MS
[M+H]+661.4, Rf=0.43 (Hex:EtOAc=2:1). H.sup.1 NMR
(CDCl.sub.3,.delta. ppm): 0.12 (s, 6H), 0.67-0.72 (s, 9H), 1.43 (s,
9H), 1.55-1.59 (m, 1H), 1.81-1.95 (m, 2H), 2.68-2.93 (m, 5H),
3.15-3.72 (m, 4H), 3.80 (s, 3H), 4.01-4.21 (m, 1H), 4.91-5.02 (m,
1H), 6.55-6.60 (m, 1 H), 6.70-6.78 (m, 2H), 7.25-7.38 (m, 3H),
7.60-7.73 (m, 1 H), 7.83-7.92 (m, 2H), 8.41-8.58 (m, 2H).
EXAMPLE 215
Preparation of
4-{2-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}m-
ethyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid
[0529] 799
[0530] Using the procedures outlined in Examples 208-211, the
compound of Example 214 was converted to the title compound. MS
[M+H]+432.2, Rf=0.5 (CH.sub.2Cl.sub.2:MeOH=7:3) H.sup.1 NMR
(MeOH-d4, .delta. ppm): 1.66-1.80 (1H, m), 2.01-2.12 (1H, m),
2.82-2.92 (6H, m), 3.18-3.30 (6H, m), 4.32 (1H, t), 5.10 (1H, dd),
6.72 (1H, d), 6.85-6.88 (2H, m), 7.16 (2H, d), 7.48 (1H, dd), 7.84
(2H, d), 7.94 (1H, d), 8.51 (1H, d), 8.63 (1H, s)
EXAMPLE 216
Preparation of
3-{2-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}m-
ethyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid
[0531] 800
[0532] Using the procedures outlined in Examples 208-211, the
compound of Example 215 was converted to the title compound. MS
[M+H]+432.2, Rf=0.5 (CH.sub.2C.sub.2:MeOH=7:3) H.sup.1 NMR
(MeOH-d4, .delta. ppm): 1.66-1.80 (1H, m), 1.99-2.12 (1H, m),
2.80-2.92 (6H, m), 3.18-3.30 (6H, m), 4.32 (1H, t), 5.10 (1H, dd),
6.72 (1H, d), 6.85-6.88 (2H, m), 7.15-7.17 (2H, m), 7.46 (1H, dd),
7.81-7.85 (2H, m), 7.94 (1H, d), 8.51 (1H, d), 8.63 (1H, s)
EXAMPLE 217
Preparation of
N-benzyl-N-{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methy-
l}amine
[0533] 801
[0534] In a 30 L reaction vessel,
N-benzyl[(2R)-3,4-dihydro-2H-chromen-2-y- l]methanamine
hydrobromide (2173 g, 6.5 moles, 1.0 eq.) was suspended in 11.4 L
formic acid. The suspension was cooled to 16.degree. C., then
bromine (1071 g, 6.7 moles, 1.03 eq.) was added over a 60 minutes,
maintaining the reaction temperature between 15 and 16.degree. C.
After 70 minutes, a HPLC probe indicated the reaction to be
complete. To the reaction mixture was then added 15.6 L water
(temperature increased to 21.degree. C). The light reaction mixture
was then stirred for 30 minutes at room temperature, then the
product was filtered and washed with 3.9 L water. The 3.14 kg of
light gray moist product was then suspended in 9.75 L
dichloromethane. To this suspension was added 13 L 1M NaHCO.sub.3.
Foaming ensued and the suspension became a bi-phasic solution. The
aqueous phase was separated (14.5 L; pH=8) and the organic phase
was washed with 6.5 L water. The phases were separated and the
organic phase evaporated at 45.degree. C. to yield 1820 g of
N-benzyl-N-{[(2R)-6-bromo--
3,4-dihydro-2H-chromen-2-yl]methyl}amine.
EXAMPLE 218
Preparation of 4-bromo-N-(2-pyrimidinyl)benzene-sulfonamide
[0535] 802
[0536] A mixture of 4-bromobenzene sulfonyl chloride (3.0 g, 11.74
mmol) and 2-aminopyrimidine (1.17 g, 12.3 mmol, 1.05 eq) in
anhydrous pyridine (23 mL) was stirred at 50.degree. C. for 17
hours. The reaction was quenched with 2N aqueous hydrochloric acid
(100 mL) and the resultant reaction mixture was extracted with
ethyl acetate (2.times.150 mL). The combined organic layers were
washed with water (1.times.100 mL) and brine (1.times.100 mL),
dried (Na.sub.2SO.sub.4), filtered, and evaporated under reduced
pressure. Recrystallization from ethyl acetate--dichloromethane
gave the desired product as a white solid (2.95 g, 80%). LC-MS (ES
MH.sup.+=314/316); TLC (R.sub.f=0.42, 75% ethyl
acetate--hexane).
[0537] Using the procedure outline in Example 208 and the
appropriate amine and sulfonyl chloride, the following sulfonamides
were prepared.
9TABLE 9 Example No. Structure 219 803 220 804 221 805 222 806 223
807 224 808 225 809 226 810 227 811 228 812 229 813 230 814 231 815
232 816 233 817 234 818 235 819 236 820 237 821 238 822 239 823 240
824 241 825 242 826 243 827 244 828 245 829 246 830
EXAMPLE 247
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyr-
idinyl)ethyl[((2R)-6-{4-[(2-pyrimidinylamino)sulfonyl]phenyl}-3,4-dihydro--
2H-chromen-2-yl)methyl]carbamate
[0538] 831
[0539] A solution of the compound of Example 81, (1.08 g, 1.73
mmol) in toluene (10 mL) and ethanol (10 mL) was degassed with
argon for 10 minutes. At this time, the compound of Example 218
(815 mg, 2.59 mmol) was added followed by
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropall- adium(II)
complex with dichloromethane (1:1) (98 mg, 0.12 mmol) and 2M
aqueous Na.sub.2CO.sub.3 (8.5 mL). The reaction was bubbled with
argon for another 10 minutes and then heated to 80.degree. C.
overnight. The reaction was diluted with ethyl acetate, washed with
water, brine, and dried over magnesium sulfate. The solvent was
removed at reduced pressure and the residue was coated on silica.
The silica coated product was purified on the MPLC (Biotage) with
30-100% ethyl acetate in hexanes then 2% methanol in methylene
chloride to afford 796 mg (1.09 mmol, 63%) of product. LC-MS (ES
MH.sup.+=732, Rt=3.27 min); TLC (R.sub.f=0.31,100% ethyl
acetate).
EXAMPLE 248
Preparation of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl[((2
R)-6-{3-[(2-pyrimidinylamino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl-
)methyl]carbamate
[0540] 832
[0541] A solution of the compound of Example 247 (796 mg, 1.09
mmol) in tetrahydrofuran (20 mL) was treated with a 1.0 M solution
of tetrabutylammonium fluoride in tetrahydrofuran (4.4 mL, 4.40
mmol). The reaction was stirred at room temperature for 2 hours. At
this time, the product was coated on silica, concentrated at
reduced pressure, and purified on the MPLC (Biotage) with 2-4%
methanol in methylene chloride to afford 650 mg (1.05 mmol, 96%) of
the desired product. TLC (R.sub.f=0.13, 100% ethyl acetate).
EXAMPLE 249
[0542] Method A. Preparation of
4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl-
)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzene-
sulfonamide 833
[0543] A solution of the compound of Example 248 (1.32 g, 2.13
mmol) in ethyl acetate (20 mL) and methylene chloride (2 mL) was
treated with 4 N HCl in 1,4-dioxane (5.5 mL, 22.0 mmol). A
suspension was formed and was allowed to stir at room temperature
under argon overnight. The reaction was then diluted with diethyl
ether and decanted. The solid was rinsed several times with diethyl
ether and dried on high vacuum to afford 1.13 g (1.80 mmol, 85%) of
product as the hydrochloride salt. .sup.1H-NMR (CD.sub.3OD-d.sub.6)
.delta. 9.04 (s, 1H), 8.88 (d, J=5.7 Hz, 1H), 8.79 (d, J=8.1 Hz, 1
H), 8.44 (d, J=4.8Hz, 2H), 8.17 (dd, J=5.8 Hz, 8.0 Hz, 1H), 8.09
(d, J=8.7 Hz, 2H), 7.73 (d, J=8.9 Hz, 2H), 7.46-7.42 (m, 2H),
7.02-6.96 (m, 2H), 5.44 (dd, J=3.0 Hz, 10.5 Hz, 1H), 4.50 (t, J=9.8
Hz, 1H), 3.62-3.35 (m, 4H), 3.02-2.94 (m, 2H), 2.21-2.14 (m, 1H),
1.87-1.80 (m, 1H); LC-MS (ES MH.sup.+=518), Rt=1.05 min.
[0544] Method B. Preparation of
4-[(2S)-2-({[-2-hydroxy-2-(3-pyridinyl)eth-
yl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulf-
onamide 834
[0545] Starting with the
(2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7,
Method B) and 2-amino-1-(3-pyridinyl)ethanol dihydrochloride and
following the procedures described in Examples 247-248 and Method A
above, the title compound was prepared. .sup.1H NMR (CD.sub.3OD)
.delta. 9.10 (s, 1 H), 8.93-8.85 (m, 1 H), 8.61 (d, J=5.2 Hz, 2 H),
8.55 (d, J=4.6 Hz, 1 H), 8.23-8.17 (m, 1 H), 8.11 (d, J=8.0 Hz, 1
H), 7.74 (d, J=8.3, 1 H), 7.44 (s, 1 H), 7.12-7.08 (m, 1 H),
7.06-7.01 (m, 1 H), 5.58-5.53 (m, 1 H), 4.60-452 (m, 1 H),
3.75-3.50 (m, 3 H), 3.52-3.41 (m, 1 H), 3.08-2.88 (m, 2 H),
2.22-2.18 (m, 1 H). 1.90-1.75 (m, 1 H). LC-MS m/z 518.2 (MH.sup.+),
Rt=0.71 minutes.
[0546] Using the procedures described in Examples 247-248, and the
starting materials described in Examples 218-246, the following
compounds were prepared:
10TABLE 10 Example MS RT (min, No. Structure [M + H.sup.+] LC-MS)
250 835 518 1.01 251 836 585 1.91 252 837 599 1.94 253 838 517 1.53
254 839 517 1.44 255 840 570 1.96 256 841 541 2.02 257 842 541 2.02
258 843 570 1.94 259 844 586 2.04 260 845 517 1.55 261 846 518 1.37
262 847 625 2.14 263 848 642 2.17 264 849 558 2.01 265 850 523 1.55
266 851 653 2.32 267 852 578 1.95 268 853 532 1.35 269 854 562 1.53
270 855 608 1.92 271 856 592 1.66 272 857 548 1.3 273 858 562 1.52
274 859 662 2.14 275 860 616 1.74 276 861 573 2.07 277 862 571 1.94
278 863 603 2.03 279 864 517 1.23 280 865 588 1.87
EXAMPLE 281
tert-Butyl
{(2S)-6-[3-(aminosulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}m-
ethyl
[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]carbam-
ate
[0547] 866
[0548] The solution of Na.sub.2CO.sub.3 (2 N, 6 mL), toluene (6
mL), and ethanol (6 mL) was degassed for 10 minutes. Then the
compound of Example 81 (1001 mg, 1.62 mmol),
3-bromobenzenesulphonamide (458 mg, 1.94 mmol) and PdCl.sub.2(dppf)
(132 mg, 0.16 mmol) were added to the above solution and it was
degassed for another 5 minutes. Then, the reaction mixture was
heated to reflux overnight. After it was allowed to cool down, the
reaction mixture was poured into water and was extracted with
EtOAc. The combined organic layer was washed by water, brine, dried
over Na.sub.2SO.sub.4, and concentrated. Chromatography with 20%
-30% ethyl acetate in hexane provided the title compound (670 mg)
as a pale yellow oil. ESLC-MS: m/z=654 (MH.sup.+); 1H NMR
(MeOH-d.sub.4): 8.576-8.451 (m, 2H), 8.077 (s, 1H),
7.906.about.7.752 (m, 3H), 7.565 (t, 1H), 7.459 (m, 1H), 7.383(m,
2H), 6.813 (d, 1H), 5.185.about.5.050 (m, 1H), 4.251 (t, 1H),
3.772.about.3.348 (m, 4H), 2.879 (m, 2H), 2.045 (m, 1 H), 1.741 (m,
1 H), 1.447(d, 9H), 0.897 (s, 9H), 0.083 (s, 3H), -0.102 (s,
3H).
EXAMPLE 282
tert-Butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl{[(-
2S)-6-(3-}[(methoxyacetyl)amino]sulfonyl}phenyl)-3,4-dihydro-2H-chromen-2--
yl]methyl}carbamate
[0549] 867
[0550] A solution of the compound of Example 281 (60 mg, 0.091
mmol), methoxyacetic acid (13 mg, 0.13 mmol), EDCI (26 mg, 0.14
mmol), and DMAP (11 mg, 0.091 mmol) in CH.sub.2Cl.sub.2 (1.5 mL)
was stirred at room temperature overnight. The reaction mixture was
concentrated down and the crude product was purified by preparative
TLC plate with CH.sub.2Cl.sub.2: MeOH: NH.sub.4OH (90:15:2) to
obtain (60 mg). ESLC-MS: m/z=725 (MH.sup.+); .sup.1H NMR
(MeOH-d.sub.4): 8.566.about.8.439 (m, 2H), 8.077 (s, 1 H),
7.889.about.7.780 (m, 1H), 7.675 (m, 1H), 7.453 (m, 2H), 7.313(m,
2H), 6.767 (d, 1H), 5.180.about.5.035 (m, 1H), 4.220 (s, b, 1H),
3.907 (s, 2H), 3.760.about.3.333 (m, 4H), 2.835 (m, 2H), 2.041 (m,
1H), 1.711 (m, 1H), 1.445 (d, 9H), 0.892 (s, 9H), 0.076 (s, 3H),
-0.109 (s, 3H).
EXAMPLE 283
3-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-
-2H-chromen-6-yl]-N-(methoxyacetyl)benzenesulfonamide
[0551] 868
[0552] Using the procedure described in Example 249, the title
compound was prepared. ESLC-MS m/z=512 (MH+), HPLC retention
time=1.53 min.
[0553] Using the procedures described in Examples 281-283, the
compounds described below were similarly prepared.
11TABLE 11 Example MS RT (min, No. Structure [M + H .sup.+] LC-MS)
284 869 550.1 1.97 285 870 508.2 1.75 286 871 526.2 1.89 287 872
528.2 0.54 288 873 618.1 2.04 289 874 538.3 0.36 290 875 510.2 0.25
291 876 512.2 0.21 292 877 524 2.01 293 878 574 1.86 294 879 544
1.55 295 880 562 1.93 296 881 558 2.01 297 882 558 2.01 298 883 574
2.18 299 884 558 2.13 300 885 573 2.15 301 886 577 2.27 302 887 577
2.26 303 888 574 1.94 304 889 525 0.76 305 890 496 1.57
EXAMPLE 306
Preparation of
1-(4-bromophenyl)-2-[(phenyl)sulfonyl]ethan-1-one
[0554] 891
[0555] To benzenesulfonyl chloride (0.5 mL, 3.92 mmol) in 4:1 v/v
tetrahydrofuran--water (20 mL) was added powdered zinc (282 mg,
4.31 mmol, 1.1 eq.) followed by 4-bromophenacyl bromide (1.31 g,
4.70 mmol, 1.2 eq.). The reaction mixture was stirred at room
temperature for 17 hours. The volatile solvent was evaporated under
reduced pressure and poured into water. The reaction was extracted
with ethyl acetate (2.times.150 mL), and the combined organic
layers were washed with brine (1.times.100 mL), dried (MgSO.sub.4),
filtered, and evaporated under reduce pressure. The crude product
was purified using MPLC (Biotage) eluted with 5:1 v/v hexane--ethyl
acetate. Crystallization from dichloromethane--hexane gave the
desired product as a white fluffy solid (486 mg, 36.6% yield). MS
LC-MS (ES MH.sup.+=340); TLC (R.sub.f=0.30, 25% ethyl
acetate--hexane)
EXAMPLE 307
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyr- idinyl)ethyl
[((2R)-6-{4-[(phenylsulfonyl)acetyl]phenyl}-3,4-dihydro-2H-ch-
romen-2-yl)methyl] carbamate
[0556] 892
[0557] The procedure was analogous to that described in Example 247
except 1-(4-bromophenyl)-2-[(phenyl)sulfonyl]ethan-1-one was used
instead of 4-bromo-N-(2-pyrimidinyl)benzene-sulfonamide. TLC
(R.sub.f=0.16, 40% ethyl acetate--hexane); LC-MS (ES MH.sup.+=757),
Rt=3.70 min.
EXAMPLE 308
Preparation of
1-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}m-
ethyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-(phenylsulfonyl)ethanone
dihydrochloride
[0558] 893
[0559] Using the procedure described in Examples 248 and 249, the
title compound was prepared. .sup.1H-NMR (CD.sub.3OD-d.sub.6)
.delta. 9.02 (s, 1H), 8.86 (d, J=5.6 Hz, 1H), 8.73 (d, J=8.0 Hz,
1H), 8.15-8.08 (m, 2H), 7.92-7.41 (m, 10H), 7.02 (d, J=9.0 Hz, 1H),
5.44 (dd, J=2.9 Hz, 10.7 Hz, 1H), 4.52 (t, J=10.2 Hz, 1H),
3.65-3.33 (m, 6H), 3.15-2.89 (m, 2H), 2.22-2.15 (m, 1H), 1.93-1.80
(m, 1H); LC-MS (ES MH.sup.+=543), Rt=2.06 min.
[0560] Using the procedures described in Examples 306-308 and using
the appropriate sulfonyl chlorides, the following compounds were
similarly prepared.
12TABLE 12 Example MS RT (min, No. Structure [M + H ]+ LC-MS) 309
894 557 2.06 310 895 578 1.83 311 896 543 2.06
EXAMPLE 312
Preparation of
1-(3-bromophenyl)-5-hydroxy-4-methyl-1,2-dihydro-3H-pyrazol-
-3-one
[0561] 897
[0562] To a suspension of 1-(3-bromophenyl)hydrazine hydrochloride
(1.0 g, 4.47 mmol) in ethanol (8.9 mL) was added dropwise 2.0 M
sodium ethoxide in ethanol (0.77 mL, 9.84 mmol, 2.2 eq.). Diethyl
2-methylmalonate (0.85 mL, 4.92 mmol, 1.1 eq.) was then added. The
reaction mixture was stirred at 90.degree. C. for 16 hours and then
quenched with 2 N aqueous hydrochloric acid (50 mL). The reaction
was extracted with ethyl acetate (3.times.50 mL), and the combined
organic layers were dried (MgSO.sub.4), filtered, and evaporated
under reduced pressure. Purification using MPLC (Biotage) eluted
with 3:1 V/V ethyl acetate--hexane gave the desired product as a
white solid (125 mg, 0.46 mmol, 10.4% yield). MS LC-MS (ES
MH.sup.+=269/271); TLC (R.sub.f=0.10, 50% ethyl
acetate--hexane).
EXAMPLE 313
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyr- idinyl)ethyl
({(2S)-6-[3-(4-hydroxy-4-methyl-3,5-dioxo-1-pyrazolidinyl)phe-
nyl]-3,4-dihydro-2H-chromen-2-yl}methyl)carbamate
[0563] 898
[0564] Using the procedures described in Example 247, Example 312
was converted to the title compound. LC-MS (ES MH.sup.+=783); TLC
(R.sub.f=0.19, 20% methanol--dichloromethane).
EXAMPLE 314
Preparation of
4-hydroxy-1-{3-[(2S)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)eth-
yl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-4-methyl-3,5-pyrazoli-
dinedione dihydrochloride
[0565] 899
[0566] Using the procedure described in Examples 248 and 249, the
title compound was prepared. .sup.1H-NMR (CD.sub.3OD-d.sub.6)
.delta. 8.96 (s, 1H), 8.84 (d, J=5.4 Hz, 1H), 8.64 (d, J=8.1 Hz,
1H), 8.07 (dd, J=8.07Hz, 6.0 Hz, 1H), 7.91 (s, 1H), 7.58 (dt,
J=7.2Hz, 2.1 Hz, 1H), 7.49 to 7.41 (m, 4H), 7.00 (d, J=9.6 Hz,
1H),5.38 (dd, J=10.8 Hz, 2.7 Hz, 1H), 4.48 (t, J=7.2 Hz, 1H), 3.65
to 3.35 (m, 4H), 3.13 to 2.95 (m, 3H), 2.19 to 2.14 (m, 1H), 1.87
to 1.75 (m, 1H), 1.70 to 1.64 (m, 1H), 1.51 (s, 3H), 1.44 to 1.28
(m, 2H); LC-MS (ES MH.sup.+=489), Rt=1.10 min.
EXAMPLE 315
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyr- idinyl)ethyl
{[(2R)-6-(5-nitro-2-pyridinyl)-3,4-dihydro-2H-chromen-2-yl]me-
thyl}carbamate
[0567] 900
[0568] The procedure was analogous to that of Example 247 except
methyl 2-chloro-5-nitropyridine was used instead of
3-bromo-N-(2-pyrimidinyl)ben- zene-sulfonamide. LC-MS (ES
MH.sup.+=621), Rt=3.68 min; TLC (R.sub.f=0.05, 25% ethyl
acetate--hexane).
EXAMPLE 316
Preparation of tert-butyl
[(2R)-6-(5-amino-2-pyridinyl)-3,4-dihydro-2H-chr-
omen-2-yl]methyl[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)et-
hyl]carbamate
[0569] 901
[0570] A dry flask under argon was charged with 10% Pd on C (50 mg)
and ethanol (10 mL) followed by the addition of Example 315 (700
mg, 1.13 mmol). The reaction was stirred under hydrogen (1 atm)
overnight. TLC analysis showed complete reaction. The reaction was
then filtered through celite and the filtrate was concentrated at
reduced pressure. The crude product was then purified on the MPLC
(biotage) with 100% ethyl acetate to afford the desired product
(610 mg, 91%). LC-MS (ES MH.sup.+=591), Rt=2.57 min; TLC
(R.sub.f=0.27, 100% ethyl acetate).
EXAMPLE 317
Preparation of
(1R)-2-({[(2R)-6-(5-amino-2-pyridinyl)-3,4-dihydro-2H-chrom-
en-2-yl]methyl}amino)-1-(3-pyridinyl)ethanol tetrahydrochloride
[0571] 902
[0572] Using the procedure described in Examples 248 and 249, the
title compound was prepared. .sup.1H-NMR (CD.sub.3OD-d.sub.6)
.delta. 9.06 (s, 1H), 8.89 (d, J=5.6 Hz, 1H), 8.82 (d, J=7.9 Hz,
1H), 8.18 (dd, J=6.1 and 8.2 Hz, 1H), 7.96-7.91 (m, 2H), 7.75 (dd,
J=2.6 Hz and 9.2 Hz, 1H), 7.60-7.56 (m, 2H), 7.14 (d, J=8.1 Hz,
1H), 5.49 (d, J=10.2 Hz, 1H), 4.59 5 (t, J=8.5 Hz, 1H), 3.75-3.36
(m, 4H), 3.13-2.92 (m, 2H), 2.26-2.20 (m, 1H), 1.91-1.84 (m, 1H);
LC-MS (ES MH.sup.+=377), Rt=0.70 min.
EXAMPLE 318
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyr-
idinyl)ethyl[((2R)-6-{5-[(phenylsulfonyl)amino]-2-pyridinyl}-3,4-dihydro-2-
H-chromen-2-yl)methyl]carbamate
[0573] 903
[0574] A solution of Example 316 (80 mg, 0.135 mmol) and benzene
sulfonyl chloride (41 mg, 0.233 mmol) in pyridine (1.5 mL) was
stirred at 50.degree. C. overnight. The reaction was diluted with
ethyl acetate, washed with water, brine, and dried over magnesium
sulfate. The crude product was coated on silica and purified on the
MPLC (Biotage) with 40-70% ethyl acetate in hexanes to afford the
desired product (91 mg, 92%). LC-MS (ES MH.sup.+=731), Rt=3.32 min,
TLC R.sub.f=0.25 60% ethyl acetate in hexanes).
EXAMPLE 319
Preparation of
N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}m-
ethyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide
trihydrochloride
[0575] 904
[0576] Using the procedure described in Examples 248 and 249,
Example 318 was converted to the title compound. .sup.1H-NMR
(CD.sub.3OD-d.sub.6) .delta. 9.05 (s, 1H), 8.88 (d, J=5.2 Hz, 1H),
8.79 (d, J=7.8 Hz, 1H), 8.43 (d, J=1.7, 1H), 8.18-7.90 (m, 5H),
7.70-7.55 (m, 5H), 7.15 (d, J=8.3 Hz, 1H), 5.47 (d, J=9.2 Hz, 1H),
4.60 (t, J=10.0 Hz, 1H), 3.67-3.32 (m, 4H), 3.11-2.92 (m, 2H),
2.26-2.19 (m, 1H), 1.91-1.84 (m, 1H); LC-MS (ES MH.sup.+=517),
Rt=1.70 min.
[0577] Using the procedures described in Examples 318 and 319, and
using the appropriate acyl or sulfonyl chloride, the following
compounds were prepared.
13TABLE 13 Example MS RT (min, No. Structure [M + H+] LC-MS) 320
905 551 1.98 321 906 455 0.8 322 907 481 1.41 323 908 419 0.74
EXAMPLE 324
Preparation of
3-((1R)-1-hydroxy-2-{[((2R)-6-{3-[({[(4-methylphenyl)aminol-
carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)
methyl]amino}ethyl)pyridine hydrochloride
[0578] 909
[0579] To a stirred solution of Example 281 (45 mg) in
dichloroethane (10 mL), were added Et.sub.3N (0.014 mL) and
4-methylphenyl isocyanate (0.013 mL). Stirring was continued at
room temperature over a 2-3 hour period. The solvent was removed
under reduced pressure. Crude product was purified by combiflash
column chromatography to give the free base of the desired product
(27 mg, 50% yield). This material was treated with HCl (4 M) in
dioxane and stirred at room temperature overnight. The solvent was
removed under reduced pressure to provide the crude product, which
was purified by preparative HPLC-to provide the title compound. MS
[M+H]+ 573.21, Rf=0.68 (CH2Cl2:MeOH=50:50); H.sup.1 NMR
(MeOH-d4,.delta. ppm): 2.25 (s, 3H), 2.85-3.08 (m, 2H), 3.38-3.67
(m, 6H), 4.50 4.54(m, 1H), 5.45-5.47 (m, 1H), 7.04-7.07 (m, 4H),
7.24 (d, 2H, J=6.3 Hz), 7.40 (dd, 1H, J=6.3 Hz), 7.42-7.45 (m, 2H),
7.63 (t, 1H, J=6.0 Hz), 7.87 (d, 1H, J=6.0 Hz), 7.93 (d, 1H, J=6.0
Hz), 8.10-8.20 (m, 1H), 8.22 (s, 1H), 8.78-8.79 (m, 1H).
[0580] Using the procedures outline in Examples 281 and 324, the
following compounds were similarly prepared.
14TABLE 14 Ex- ample MS HPLC TLC No. Structure [M + H]+ (RT) Rf
(solvent) 325 910 654.3 0.22 (7:3 ethyl acetate/hexanes) 326 911
573.2 0.25 (1:9 MeOH CH2Cl2) 327 912 577.3 0.21 (1:9 MeOH CH2Cl2)
328 913 559.3 0.23 (1.9 MeOH CH2Cl2) 329 914 565.37 0.31 (1:9 MeOH
CH2Cl2) 330 915 629.34 0.21 (1:9 MeOH CH2Cl2) 331 916 595.42 0.22
(1:9 MeOH CH2Cl2) 332 917 559.2 8.2 min 333 918 577.2 9.3 334 919
589.2 6.6 335 920 592.2 10.1 336 921 577.2 6.4 337 922 627.2 5.7
338 923 577.31 0.23 (1:9 MeOH CH2Cl2) 339 924 525.32 0.27 (1:9 MeOH
CH2Cl2) 340 925 593.31 0.31 (1:9 MeOH CH2Cl2)
EXAMPLE 341
Preparation of 3,4-Dimethylphenyloxirane
[0581] 926
[0582] The procedure was based on methods described by Brandes and
Jacobsen, (Tetrahedron Asym. 8:3927,1997); and Kaufman (Syn.
Commun. 23:473,1993). A solution of trimethylsulfonium
methylsulfate (3.95 g, 0.021 mol) in 8 mL water was added slowly to
a biphasic mixture of 50% NaOH (20 mL), 3,4-dimethyl-benzaldehyde
(1.34 g, 0.01 mmol), tetrabutylammonium bromide (0.025 g, 0.0782
mmol), and CH.sub.2Cl.sub.2 (26 mL). The reaction was heated at
50.degree. C. for 13 hours and then cooled to room temperature. The
reaction was diluted carefully with brine (50 mL) and diethyl ether
(3.times.70 mL), then filtered to remove the solids. The aqueous
layer was extracted with diethyl ether (3.times.70 mL), and the
combined organic layers were washed with brine (50 mL) and dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to
afford the product 3,4-dimethylphenyl oxirane as a light yellow oil
(1.15 g, yield 78%). TLC Rf=0.9 (1:2 EtOAc/Hexane); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.39 (s, 1 H), 7.21 (d, 1 H), 7.19
(s, 1 H), 3.80 (m, 1 H), 3.17 (m, 1 H), 2.80 (m, 1 H), 2.23 (s, 6
H).
EXAMPLE 342-354
General Procedure for Coupling Epoxides
(4-[(2R)-2-({[2-(3,4-dimethylpheny-
l)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic
Acid)
[0583] Step 1: Condensation of the Chroman Amine with Epoxides
[0584] Into an 8-mL screw-cap vial were dispensed 200 .mu.L of a
0.5 M solution of
6-(4-methoxycarbonylphenyl)-(R)-chroman-2-methylamine (Example 19
free base, 0.01 mmol) and 200 .mu.L of the appropriate epoxide
solution (commercial or prepared as in Example 341, 0.01 mmol).
Dioxane (500 .mu.L) and water (100 .mu.L) were then added to each
vial, and the mixture was heated at 80.degree. C. with mixing by
orbital shaking for 2 days. After the mixture was allowed to cool
to room temperature, the solvent was removed under reduced pressure
by using a multiple sample evaporator (GeneVac).
[0585] Step 2: Hydrolysis of the Methyl Ester
[0586] The residue obtained from the previous procedure was heated
in 1 mL 2 M lithium hydroxide solution in 3:1 methanol/water at
60.degree. C. overnight. After allowing the reaction mixture to
cool to room temperature, 1.1 mL hydrochloric acid (2 N) was slowly
added to each vial. Precipitate was formed in the vial. The solvent
was removed under reduced pressure by using a multiple sample
evaporator (GeneVac). The residue was dissolved in 1 mL MeOH, and
then purified by preparative reversed phase HPLC, using aqueous
MeCN containing 0.1% trifluoroacetic acid as eluant.
[0587] In a typical example,
6-(4-methoxycarbonylphenyl)-(R)-chroman-2-met- hylamine and
3,4-dimethylphenyl oxirane were reacted by following the procedure
described above to provide 4-[(2R)-2-({[2-(3,4-dimethylphenyl)--
2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic
acid as the trifluoroacetate salt (17% yield). .sup.1H NMR (300
MHz, DMSO) .delta. 7.95 (d, 2 H), 7.72 (d, 2 H), 7.50 (d, 2 H),
7.15-7.00 (m, 3 H), 6.95 (m, 1 H), 4.45 (m, 2 H), 3.80 (m, 1 H),
3.30 (s, 4 H), 2.95-2.80 (m, 2 H), 2.10 (d, 6 H), 1.70 (m, 1 H);
LC-MS m/z 432 (MH.sup.+), ret. time 2.19 min.
[0588] Using the procedure outlined above, Examples 342-354 were
prepared.
15TABLE 15 Example LC/MS MS+ No. Structure RT (min) [M + H].sup.+
342 927 2.19 432 343 928 1.82 435 344 929 2.12 438 345 930 2.04 404
346 931 2.04 404 347 932 2.09 449 348 933 2.19 474 349 934 2.12 456
350 935 2.19 436 351 936 2.13 448 352 937 2.25 456 353 938 2.27 472
354 939 2.32 472
EXAMPLE 355
Preparation of
(2R)-N-{(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl-
]-2-hydroxyethyl}-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
[0589] 940
[0590] A reaction mixture containing
(2R)-6-iodo-3,4-dihydro-2H-chromene-2- -carboxylic acid (Example 7,
5.39 mmol, 1.0 eq.), (1R)-2-amino-1-[6-(2,5-d-
imethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethanol dihydrochloride (U.S.
Pat. No. 6,051,586) (6.47 mmol, 1.2 eq.),
1-(3-dimethylaminopropyl)-3-ethylcarbodi- imide hydrochloride
(EDCl, 10.8 mmol, 2.0 eq.), 1-hydroxybenzotriazole hydrate (HOBT,
10.8 mmol, 2.0 eq.), and triethylamine (16.2 mmol, 3.0 eq.) in
CH.sub.2Cl.sub.2 (30 mL) was stirred at room temperature for 18
hours. Water was added to the reaction mixture and the resulting
two-phase mixture was extracted with CH.sub.2Cl.sub.2. The combined
organic extracts were washed with water and brine, dried over
anhydrous sodium sulfate, concentrated and purified by medium
pressure column chromatography (Biotage 40S normal phase silica gel
column, CH.sub.2Cl.sub.2:MeOH=100:4). The product was obtained as a
pale yellow foam in 56% yield. MH.sup.+=518.2, RT=3.74 min.
EXAMPLE 356
Preparation of
(1R)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-({[(-
2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)ethanol
[0591] 941
[0592] To a solution of
(2R)-N{(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-p-
yridinyl]-2-hydroxyethyl}-6-iodo-3,4-dihydro-2H-chromene-2-carboxamide
(Example 355, 7.67 mmol, 1 eq.) in THF (150 mL) at room temperature
was added slowly borane-methyl sulfide complex (2M in THF, 38.4
mmol, 5.0 eq.). After completion of the addition, the reaction
mixture was heated to reflux for 2 hours and was then cooled to
room temperature. The excess borane was quenched by the dropwise
addition of EtOH (9 mL) followed by the slow addition of 2 M HCl
(40 mL). The resulting mixture was heated to reflux for 1 hour and
was then allow to cool to room temperature. The mixture was
basified with 1N NaOH and extracted with ethyl acetate. The organic
extract was washed with brine, dried over anhydrous sodium sulfate,
concentrated, and purified by medium pressure column chromatography
(Biotage 40S normal phase silica gel column, using a gradient of
1:4 hexanes:EtOAc to 1:10 MeOH:EtOAc). The product was obtained as
a pale yellow oil in 63% yield. MH.sup.+=503.9, RT=3.23 min.
EXAMPLE 357
Preparation of tert-butyl
(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridi-
nyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbam-
ate
[0593] 942
[0594] A reaction mixture containing
(1R)-1-[6-(2,5-dimethyl-1H-pyrrol-1-y-
l)-3-pyridinyl]-2-({[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-
ethanol (Example 356, 3.28 mmol, 1.0 eq.) and di-tert-butyl
dicarbonate (3.44 mmol, 1.05 eq.) in THF (15 mL) was stirred at
room temperature for 18 hours.
[0595] The solvent was evaporated and the residue was purified by
medium pressure column chromatography (Biotage 40S normal phase
silica gel column, 2:1 hexanes:EtOAc). The product was obtained as
a beige foam in 68% yield. MH.sup.+=603.9, RT=4.43 min.
EXAMPLE 358
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,-
5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-iodo-3,4-dihydro-2H-c-
hromen-2-yl]methyl}carbamate
[0596] 943
[0597] A mixture of tert-butyl
(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-p-
yridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}c-
arbamate (Example 357, 7.5 g, 12.4 mmol), TBDMSCl (2.25 g, 14.9
mmol), and imidazole (2.10 g, 30.9 mmol) in DMF (10 mL) was stirred
at room temperature under argon for 24 hours. The reaction mixture
was then poured into a saturated NaHCO.sub.3 solution (50 mL). The
mixture was extracted with ether (100 mL.times.2). The ether layer
was washed with water (50 mL) and dried over anhydrous sodium
sulfate. Removal of the solvent in vacuo afforded a near white
syrup which was purified by column chromatography (silica gel,
hexanes/ethyl acetate (5/1, v/v)) and gave the desired compound as
a colorless oil (6.5 g, 72%).
EXAMPLE 359
Preparation of ethyl
(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethy-
l-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-
-chromene-6-carboxylate
[0598] 944
[0599] A solution of tert-butyl
(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3--
pyridinyl]-2-hydroxyethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}-
carbamate (Example 357,1.72 mmol, 1.0 eq.) in EtOH (6.5 mL) was
treated with Pd(OAc).sub.2 (0.09 mmol, 0.05 eq.) and triethylamine
(4.31 mmol, 2.5 eq.). The reaction mixture was vigorously stirred
and degassed with argon. This suspension was heated to reflux for
18 hours under 1 atmosphere of carbon monoxide. The resulting
solution was cooled to room temperature and filtered through a
Celite.RTM. pad, washing with more EtOH. The filtrate was
concentrated and purified by medium pressure column chromatography
(Biotage 40S normal phase silica gel column, using a gradient of
8:1 to 2:1 hexanes:EtOAc). The product was obtained as a colorless
oil in 62%. MH.sup.+=550.3, 3.79 min.
EXAMPLE 360
Preparation of
(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-p-
yrrol-1-yl)-3-Pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chrom-
ene-6-carboxylic Acid
[0600] 945
[0601] A solution of ethyl
(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-d-
imethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihy-
dro-2H-chromene-6-carboxylate (Example 359, 0.21 mmol, 1.0 eq.) and
1N NaOH (0.63 mmol, 3.0 eq.) in EtOH (2 mL) was heated to reflux
for 1.5 hours. The reaction mixture was allowed to cool to room
temperature and was concentrated in vacuo to afford a residue that
was purified by medium pressure column chromatography (Biotage 40S
normal phase silica gel column, 100:5 CH.sub.2Cl.sub.2:MeOH). The
product was obtained as a white foam in 72% yield. MH.sup.+=522.3,
RT=3.11 min.
EXAMPLE 361
Preparation of ethyl
N-({(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dim-
ethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydr-
o-2H-chromen-6-yl}carbonyl)glycinate
[0602] 946
[0603] The product was obtained in 44% yield via a coupling
reaction between
(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dimethyl-1H-pyrrol--
1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydro-2H-chromene-6--
carboxylic acid (Example 360) and glycine ethyl ester hydrochloride
utilizing the method described for Example 355; MH.sup.+=607.3,
RT=3.18 min.
EXAMPLE 362
Preparation of
N-{[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]a-
mino}methyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}glycine
[0604] 947
[0605] A mixture of ethyl
N-({(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,-
5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-d-
ihydro-2H-chromen-6-yl}carbonyl)glycinate (Example 361, 0.08 mmol,
1.0 eq.) in EtOH/H.sub.2O (0.8 mL /0.2 mL) was treated with 2 N HCl
(0.42 mmol, 5.0 eq), followed by hydroxylamine hydrochloride (0.084
mmol, 10.0 eq.). The resulting reaction mixture was heated at
reflux for 18 hours. Solvents were evaporated in vacuo and the
brown residue was purified by reverse phase HPLC. The product was
obtained as the TFA salt in 15%. MH.sup.+=401.1, RT=0.79 min.
[0606] Following the procedures described above for Examples
361-362, and using Example 360 and the appropriate amino acid
esters as starting materials, the following compounds were
similarly prepared:
16TABLE 16 948 Example RT (LC- MS No. R" MS min,) [M + H].sup.+ 363
949 0.79 441.2 364 950 0.78 455.2 365 951 0.76 492.2 366 952 0.77
367 953 0.62 441.3 368 954 1.26 505.2 369 955 1.52 491.2
EXAMPLE 370
Preparation of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,-
5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl--
1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate
[0607] 956
[0608] The product was prepared from tert-butyl
(2R)-2-{[tert-butyl(dimeth-
yl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-
-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 358)
according to the method described for Example 81.
EXAMPLE 371
Preparation of methyl
4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-{[tert-buty-
l(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethy-
l}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate
[0609] 957
[0610] Argon was bubbled through a solution of tert-butyl
(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl-
)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)--
3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 370, 395 mg,
0.55 mmol) in toluene (15 mL) and 1,4-dioxane (3 mL) for 10
minutes. Bis(diphenylphosphino)ferrocene-palladium (40 mg) and
methyl 4-iodobenzoate (216 mg, 0.83 mmol) were added, and bubbling
with argon was continued for another 5 minutes. 2 N aq. sodium
carbonate solution (3 mL, 6 mmol) was added and the reaction
mixture was heated (85.degree. C.) for 16 hours. After cooling, the
mixture was filtered through a pad of silica gel and Celite.RTM.
using ethyl acetate to rinse. The filtrate was concentrated in
vacuo and then flash chromatography of the residue over silica gel
using 20% ethyl acetate/hexanes afforded 276 mg (69%) of the
desired product. The product had: .sup.1H NMR (CDCl.sub.3,
.delta.): 8.65 (d, J=20.0 Hz, 1 H), 8.13 (d, J=7.9 Hz, 2 H), 7.91
(dd, J=16.8, 8.1 Hz, 1 H), 7.67 (d, J=7.6 Hz, 2 H), 7.24-7.47 (m, 3
H), 6.93 (dd, J=8.1, 1.8 Hz, 1 H), 5.98 (d, J=3.9 Hz, 1 H), 5.23
(dd, J=43.5, 5.5 Hz, 1 H), 4.21-4.43 (m, 1 H), 4.00 (s, 3 H),
3.37-3.95 (m, 4 H), 2.84-3.09 (m, 2 H), 2.22 (s, 3 H), 2.20 (s, 3
H), 2.03-2.18 (m, 1 H), 1.74-1.91 (m, 1 H), 1.59 (d, J=10.4 Hz, 9
H), 0.99 (s, 9 H), 0.17 (s, 3 H), 0.00 (s, 3 H); mass spectroscopy
gave m/z=726.4 [M+H].sup.+ (calc'd exact mass for
C.sub.42H.sub.55N.sub.3O.sub.6Si=725.4).
[0611] Using the method described above for Example 371, the
following compounds were similarly prepared using Example 81 and
the appropriate halobenzene starting material:
17TABLE 17 Example MS HPLC No. Structure [M + H.sup.+] RT (min) 372
958 726.4 5.18 373 959 765.4 4.85 374 960 978 5.29
EXAMPLE 375
Preparation of methyl
4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dim-
ethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydr-
o-2H-chromen-6-yl}benzoate
[0612] 961
[0613] To a solution of methyl
4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-{[-
tert-butyl(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyrid-
inyl]ethyl}-amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate
(Example 371, 213 mg, 0.29 mmol) in THF (5 mL) was added a solution
of 1 M tetrabutylammonium fluoride (0.59 mL, 0.59 mmol). The
mixture was stirred at room temperature for 16 hours and then
concentrated in vacuo. Flash chromatography of the residue over
silica gel using 40% ethyl acetate/hexanes afforded 213 mg (92%) of
the desired product. The product had: .sup.1H-NMR
(CDCl.sub.3.delta.): 8.62 (s, 1 H), 8.06 (d, J=8.9 Hz, 2 H), 7.92
(d, J=7.2 Hz, 1 H), 7.58 (d, J=8.8 Hz, 2 H), 7.31-7.40 (m, 2 H),
7.22 (d, J=7.8 Hz, 1 H), 6.89 (d, J=7.9 Hz, 1 H), 5.89 (s, 2 H),
5.10-5.26 (m, 2 H), 4.21-4.50 (m, 1 H), 3.93 (s, 3 H), 3.56-3.88
(m, 4 H), 3.15-3.42 (m, 1 H), 2.78-3.04 (m, 2 H), 2.12 (s, 6 H),
1.65-1.83 (m, 2 H), 1.50 (s, 9 H).
EXAMPLE 376
Preparation of methyl
3-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-(2,5-dim-
ethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3,4-dihydr-
o-2H-chromen-6-yl}benzoate
[0614] 962
[0615] In similar fashion to that described above for Example 375,
the title compound was prepared from Example 372 and used without
further purification.
EXAMPLE 377
Preparation of methyl 4-((2R)-2-{[[(2
R)-2-(6-amino-3-pyridinyl)-2-hydroxy-
ethyl](tert-butoxycarbonyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)benzo-
ate
[0616] 963
[0617] To a solution of methyl
4-{(2R)-2-[((tert-butoxycarbonyl){(2R)-2-[6-
-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]-2-hydroxyethyl}amino)methyl]-3-
,4-dihydro-2H-chromen-6-yl}benzoate (Example 375, 162 mg, 0.26
mmol) in ethanol (4 mL) was added hydroxylamine monohydrate (182
mg, 2.65 mmol) and 2 N aq. potassium hydroxide (0.66 mL, 1.32
mmol). vThe mixture was stirred at room temperature for 70 hours
and then concentrated in vacuo. Flash chromatography of the residue
using 10% methanol/ethyl acetate afforded 80 mg (43%) of the
desired product containing trace impurities. This material was
taken on without further purification. Mass spectroscopy gave
m/z=534.3 [M+H].sup.+ (calc'd exact mass for
C.sub.30H.sub.35N.sub.3O.sub.6=533.3).
[0618] Using the method described above for Example 377 and
substituting the appropriate starting materials, the following
compounds were made and characterized:
18TABLE 18 HPLC Example MS Starting RT No. Structure [M + H.sup.+]
Material (min) 378 964 used crude 370 -- 379 965 687.4 367 3.08 380
966 658.3 368 2.95
EXAMPLE 381
Preparation of methyl
4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxye-
thyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
[0619] 967
[0620] Methyl
4-((2R)-2-{[[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl](te-
rt-butoxycarbonyl)-amino]methyl}-3,4-dihydro-2H-chromen-6-yl)benzoate
(Example 377, 80 mg, 0.15 mmol) was added to 4 M hydrochloric acid
in dioxane (3 mL, 12 mmol). The solution was stirred at room
temperature for 18 hours and then concentrated in vacuo. The
residue was purified by prep. HPLC, afforded 40 mg (62%) of the
desired product. The product had: .sup.1H NMR (CD.sub.3OD.delta.):
8.04 (d, J=8.1 Hz, 2 H); 7.89-8.03 (m, 2 H), 7.68 (d, J=7.8 Hz, 2
H), 7.42-7.49 (m, 2 H), 6.95-7.07 (m, 2 H), 5.02-5.10 (m, 1 H),
4.24-4.52 (m, 1 H), 3.91 (s, 3 H), 3.20-3.52 (m, 4 H), 2.81-3.04
(m, 2 H), 2.11-2.24 (m, 1 H), 1.74-1.92 (m, 1 H); mass spectroscopy
gave m/z=434.2 [M+H].sup.+ (calc'd exact mass for
C.sub.25H.sub.27N.sub.3O.sub.4=433.2).
[0621] Using the method described above for Example 381 and
substituting the appropriate starting materials, the following
compounds were made and characterized:
19TABLE 19 Example MS Starting HPLC No. Structure [M + H.sup.+]
Material RT (min) 382 968 434.2 372 1.95 383 969 473.3 373 1.56 384
970 444.2 374 1.46
EXAMPLE 385
Preparation of
4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]am-
ino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
[0622] 971
[0623] To a solution of methyl
4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-
-hydroxyethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate
(Example 381, 40 mg, 0.1 mmol) in THF (2 mL) and methanol (2 mL)
was added 2 M aq. lithium hydroxide (0.5 mL, 1 mmol). The mixture
was stirred at room temperature for 18 hours and then concentrated
in vacuo. Prep. HPLC of the residue afforded 10.8 mg (28%) of the
desired product. The product had: .sup.1H NMR (CDCl.sub.3,
.delta.): 7.96 (d, J=8.2 Hz, 2 H), 7.90 (d, J=2.2 Hz, 1 H),
7.49-7.56 (m, 3 H), 7.32-7.39 (m, 2 H), 6.82 (d, J=9.0 Hz, 1 H),
6.59 (d, J=8.6 Hz, 1 H), 4.70 (dd, J=8.3, 4.4 Hz, 1 H), 4.14-4.23
(m, 1 H), 2.75-3.02 (m, 6 H), 1.99-2.10 (m, 1 H), 1.70-1.85 (m, 1
H); mass spectroscopy gave m/z=420.2 [M+H].sup.+ (calc'd exact mass
for C.sub.24H.sub.25N.sub.3O.sub.4=419.2).
EXAMPLE 386
Preparation of
3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]am-
ino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic Acid
[0624] 972
[0625] The title compound was made from Example 382 and
characterized using the method described above for Example 385;
m/z=420.2 [M+H].sup.+; RT1.9 min.
EXAMPLES 387-388
Reaction of Chroman-2-Methylamines with Epoxides: Method for
Combinatorial/Parallel Synthesis
[0626] 973
[0627] The apparatus used was as described in the general
experimentals methods above. In a typical procedure, a solution of
(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine (Example 10)
and an epoxide (commercially-available or prepared as described in
WO99/32475) were freshly prepared as a 0.5 M solution in dioxane.
To each reaction well in a polypropylene reaction block was added a
solution of the desired amine (200 .mu.L, 0.1 mmol), a solution of
the desired epoxide (200 .mu.L, 0.1 mmol), and 500 .mu.L of dioxane
as well as 100 .mu.L of water. The reaction block was sealed with
rubber gaskets and clamped, then heated at 80.degree. C. for 72
hours, with mixing by rotation. After allowing the reaction block
to cool to room temperature, the block was disassembled, and the
reaction well contents were filtered into a collection 96-well
deep-well microtiter plate, washing with 2 portion of 200 .mu.L of
dioxane. The filtrate solutions were evaporated to dryness using a
multiple sample centrifugal vacuum evaporator. Products were
analyzed for purity and correct identity by LC/MS.
[0628] Utilizing the above procedures and starting from
(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methylamine (Example 10)
and the appropriate epoxide starting material, the following
compounds were prepared and characterized:
20TABLE 20 Example RT (min) MS m/z No. Structure LC/MS [M +
H].sup.+ 387 974 2.52 410 388 975 2.63 444
[0629] An embodiment of the present invention is the administration
of the compounds of this invention to a human or animal for the
treatment of beta-3 adrenergic receptor mediated conditions such as
diabetes, obesity, gastrointestinal disorders including irritable
bowel syndrome and intestinal hypermotility disorders, peptic
ulcerations, esophagitis, gastritis, and duodenitis, intestinal
ulcerations including inflammatory bowel disease, ulcerative
colitis, Crohn's disease and proctitis, and gastrointestinal
ulcerations, as well as neurogenetic inflammation such as cough and
asthma, and depression. It is also believed that the compounds of
this invention are effective in the treatment of
hyper-triglyceridemia, hypercholesterolemia and conditions of low
or high density lipoprotein levels, artherosclerotic disease and
cardiovascular disease and related conditions. Additionally, it is
also believed that the compounds of this invention are effective in
the treatment of ocular hypertension and glaucoma, and in the
treatment of urinary disorders including pollakiuria and
incontinence, as well as in the treatment of prostate disease and
as topical anti-inflammatory agents.
[0630] Therefore, the compounds of this invention are expected to
be valuable as therapeutic agents. An embodiment of this invention
includes a method of treating beta-3 adrenergic receptor mediated
conditions in a mammal which comprises administering to said mammal
a composition containing an amount of the compound of Formula I
that is effective in treating the target condition.
[0631] The specificity of the compounds of this invention as beta-3
adrenergic receptor agonists can readily be determined by
evaluating the affinity of the compound for the different beta
adrenergic receptor subtypes and comparing the activity with
various receptor subtypes affinities to discover specificity as
well as activity using standard and well-known procedures. Such a
procedure is described in more detail in the specific example
below.
EXAMPLE 389
Biological Evaluation of Compounds
[0632] The utility of the compounds of this invention can be
demonstrated by the following procedure.
[0633] Chinese hamster ovary (CHO) cells that stably express
full-length human beta-3-adrenergic receptor (Granneman et al.,
Mol. Pharmacol. 44:264-270,1993) can be used in the following
procedure. The cell line is grown in 90% F12 nutrient mixture
(HAM), 10% fetal bovine serum, 100 units/ml penicillin G sodium,
100 mg/ml streptomycin sulfate, and 2 mM L-glutamine at 37.degree.
C. in 95% air and 5% CO.sub.2. The transfected cell line is
maintained with G-418 (800 .mu.g/ml).
[0634] To test the agonist activity, cells are exposed to test
compound and then assayed for cAMP production. CHO cells (100
.mu.l) are plated at 5.times.10.sup.4 cells/well of a 96-well plate
(Costar, Cambridge, Mass.) to achieve 70% confluency the next day.
After overnight incubation at 37.degree. C., media is removed and
the cells are treated for 30 minutes at 37.degree. C. with KRP
buffer (120 mM NaCl, 5.1 mM KCl, 0.6 mM MgSO.sub.47 H.sub.2O, 0.8
mM CaCl.sub.2H.sub.2O, 12.5 .mu.M phosphate buffer, 20 .mu.M Hepes
pH 7.4) +0.2 .mu.M IBMX (100 .mu.M/well), +1% DMSO, +/- test
compounds (10 .mu.M DMSO stocks). Test compounds are assayed from
10 .mu.M to 3 nM with 3-fold serial dilutions. The control agonist,
isoproterenol (10 mM stock in 1.1 mM ascorbate), is assayed by
3-fold dilution beginning at 1 .mu.M. After a 30-minute incubation
with the test compounds, the buffer/compound mixture is removed.
The cells are lysed and cAMP levels are measured using the cAMP SPA
screening assay system (Amersham, Arlington Heights, Ill.). The
cAMP values are then plotted to determine the EC.sub.50 of each
compound tested.
[0635] In tests utilizing the above described procedure, the
compounds of the present invention were found to have beta-3
adrenergic agonist activity with levels of activity summarized in
Table 21.
21TABLE 21 Beta-3 Agonistic Activity Compounds with EC.sub.50
values Compounds with EC.sub.50 values .ltoreq.1 .mu.M >1 .mu.M
(Example No.) (Example No.) 36 39 40 41 47 42 48 43 54 45 184-188
363 192 364 193-198 365 205 367 211 215 216 249A 249B 250-280
283-305 308-311 314 317 319-340 343 344 348 352 362 366 369
381-386
[0636] Beta-3 adrenergic receptor agonists may be useful for
correcting the insulin resistance that underlies two prediabetic
states, impaired glucose tolerance (Harris, Diabetes Care
12:464-474, 1989) and impaired fasting glucose (Weyer et al.,
Diabetes 48:2197-2203,1999). The ability of a beta-3 adrenergic
receptor agonist to restore insulin sensitivity has been
demonstrated in a diabetic animal model with marked insulin
resistance. Treatment of KK-Ay/Ta diabetic obese mice with a beta-3
adrenergic receptor agonist resulted in marked improvement in the
animals' responses to insulin (Kato et al., Diabetes 50:113-122,
2001). Insulin resistance in human subjects with impaired glucose
tolerance has been treated by troglitazone, another class of
insulin sensitizers (Saltiel et al., Diabetes 45:1661-1669,1996;
Saleh et al., Diabetes Rev. 7:55-76,1999). In such studies,
improvement in the insulin responses of these subjects were
demonstrated. These overall findings support treating the insulin
resistance in prediabetic conditions with insulin sensitizers,
including beta-3 adrenergic receptor agonists, to delay or prevent
the onset of type 2 diabetes.
[0637] Based upon the above and other standard laboratory
techniques known to evaluate compound receptor site inhibition, by
standard toxicity tests and by standard pharmacological assays for
the determination of treatment of the beta-3 adrenergic receptor
mediated conditions identified above in mammals, and by comparison
of these results with the results of known medicaments that are
used to treat these conditions, the effective dosage of the
compounds of this invention can readily be determined for treatment
of each desired indication. The amount of the active ingredient to
be administered in the treatment of one of these conditions can
vary widely according to such considerations as the particular
compound and dosage unit employed, the mode of administration, the
period of treatment, the age and sex of the patient treated, and
the nature and extent of the condition treated.
[0638] The total amount of the active ingredient to be administered
will generally range from about 0.01 mg/kg to about 100 mg/kg, and
preferably from about 0.1 mg/kg to about 20 mg/kg body weight per
day. A unit dosage may contain from about 5 mg to about 1500 mg of
active ingredient, and may be administered one or more times per
day. Of course, the specific initial and continuing dosage regimen
for each patient will vary according to the nature and severity of
the condition as determined by the attending diagnostician.
[0639] The compounds of this invention may be utilized to achieve
the desired pharmacological effect by administration to a patient
in need thereof in an appropriately formulated pharmaceutical
composition. A patient, for the purpose of this invention, is a
mammal, including a human, in need of treatment for a particular
beta-3 adrenergic receptor mediated condition or disease.
Therefore, the present invention includes pharmaceutical
compositions which are comprised of a pharmaceutically acceptable
carrier and a pharmaceutically effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt or ester thereof.
A pharmaceutically acceptable carrier is any carrier which is
relatively non-toxic and innocuous to a patient at concentrations
consistent with effective activity of the active ingredient so that
any side effects ascribable to the carrier do not vitiate the
beneficial effects of the active ingredient. A pharmaceutically
effective amount of compound is that amount which produces a result
or exerts an influence on the particular condition being treated.
The compounds of Formula I may be administered with a
pharmaceutically-acceptable carrier using any effective
conventional dosage unit forms, including immediate and timed
release preparations, orally, parenterally, topically, or the
like.
[0640] For oral administration, the compounds may be formulated
into solid or liquid preparations such as capsules, pills, tablets,
troches, lozenges, melts, powders, solutions, suspensions, or
emulsions, and may be prepared according to methods known to the
art for the manufacture of pharmaceutical compositions. The solid
unit dosage forms may be a capsule which can be of the ordinary
hard- or soft-shelled gelatin type containing, for example,
surfactants, lubricants, and inert fillers such as lactose,
sucrose, calcium phosphate, and corn starch.
[0641] In another embodiment, the compounds of this invention may
be tableted with conventional tablet bases such as lactose,
sucrose, and cornstarch in combination with binders such as acacia,
cornstarch, or gelatin; disintegrating agents intended to assist
the break-up and dissolution of the tablet following administration
such as potato starch, alginic acid, corn starch, and guar gum;
lubricants intended to improve the flow of tablet granulation and
to prevent the adhesion of tablet material to the surfaces of the
tablet dies and punches, for example, talc, stearic acid, or
magnesium, calcium, or zinc stearate; dyes; coloring agents; and
flavoring agents intended to enhance the aesthetic qualities of the
tablets and make them more acceptable to the patient. Suitable
excipients for use in oral liquid dosage forms include diluents
such as water and alcohols, for example, ethanol, benzyl alcohol,
and polyethylene alcohols, either with or without the addition of a
pharmaceutically acceptable surfactant, suspending agent, or
emulsifying agent.
[0642] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient in admixture with a dispersing or wetting agent, a
suspending agent, and one or more preservatives. Suitable
dispersing or wetting agents and suspending agents are exemplified
by those already mentioned above. Additional excipients, for
example those sweetening, flavoring, and coloring agents described
above, may also be present.
[0643] The pharmaceutical compositions of this invention may also
be in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil such as liquid paraffin or a mixture of vegetable
oils. Suitable emulsifying agents may be (1) naturally occurring
gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial
esters derived form fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, (4) condensation products of said
partial esters with ethylene oxide, for example, polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0644] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil such as, for example, arachis oil,
olive oil, sesame oil, or coconut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening
agent such as, for example, beeswax, hard paraffin, or cetyl
alcohol. The suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and one
or more sweetening agents such as sucrose or saccharin.
[0645] Syrups and elixirs may be formulated with sweetening agents
such as, for example, glycerol, propylene glycol, sorbitol, or
sucrose. Such formulations may also contain a demulcent, and
preservative, flavoring, and coloring agents.
[0646] The compounds of this invention may also be administered
parenterally, that is, subcutaneously, intravenously,
intramuscularly, or interperitoneally, as injectable dosages of the
compound in a physiologically acceptable diluent with a
pharmaceutical carrier which can be a sterile liquid or mixture of
liquids such as water; saline; aqueous dextrose and related sugar
solutions; an alcohol such as ethanol, isopropanol, or hexadecyl
alcohol; glycols such as propylene glycol or polyethylene glycol;
glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4- -methanol;
ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a
fatty acid ester or glyceride; or an acetylated fatty acid
glyceride with or without the addition of a pharmaceutically
acceptable surfactant such as a soap or a detergent; suspending
agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose; or
emulsifying agent and other pharmaceutical adjuvants.
[0647] Illustrative of oils which may be used in the parenteral
formulations of this invention are those of petroleum, animal,
vegetable, or synthetic origin, for example, peanut oil, soybean
oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum,
and mineral oil. Suitable fatty acids include oleic acid, stearic
acid, and isostearic acid. Suitable fatty acid esters are, for
example, ethyl oleate and isopropyl myristate. Suitable soaps
include fatty alkali metal, ammonium, and triethanolamine salts and
suitable detergents include cationic detergents, for example,
dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and
alkylamine acetates; anionic detergents, for example, alkyl, aryl,
and olefin sulfonates, alkyl, olefin, ether, and monoglyceride
sulfates, and sulfosuccinates; nonionic detergents, for example,
fatty amine oxides, fatty acid alkanolamides, and
polyoxyethylenepolypropylene copolymers; and amphoteric detergents,
for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
[0648] The parenteral compositions of this invention will typically
contain from about 0.5% to about 25% by weight of the active
ingredient in solution. Preservatives and buffers may also be used
advantageously. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain a non-ionic
surfactant having a hydrophile-lipophile balance (HLB) of from
about 12 to about 17. The quantity of surfactant in such
formulation may range from about 5% to about 15% by weight. The
surfactant may be a single component having the above HLB or may be
a mixture of two or more components having the desired HLB.
[0649] Illustrative of surfactants used in parenteral formulations
are the class of polyethylene sorbitan fatty acid esters, for
example, sorbitan monooleate and the high molecular weight adducts
of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
[0650] The pharmaceutical compositions may be in the form of
sterile injectable aqueous suspensions. Such suspensions may be
formulated according to known methods using suitable dispersing or
wetting agents and suspending agents such as, for example, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents which may be a naturally occurring phosphatide such
as lecithin, a condensation product of an alkylene oxide with a
fatty acid, for example, polyoxyethylene stearate, a condensation
product of ethylene oxide with a long chain aliphatic alcohol, for
example, heptadecaethyleneoxycetanol, a condensation product of
ethylene oxide with a partial ester derived form a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or a
condensation product of an ethylene oxide with a partial ester
derived from a fatty acid and a hexitol anhydride, for example,
polyoxyethylene sorbitan monooleate.
[0651] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent. Diluents and solvents that may be
employed are, for example, water, Ringer's solution, and isotonic
sodium chloride solution. In addition, sterile fixed oils are
conventionally employed as solvents or suspending media. For this
purpose, any bland, fixed oil may be employed including synthetic
mono or diglycerides. In addition, fatty acids such as oleic acid
may be used in the preparation of injectables.
[0652] A composition of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable non-irritation excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are, for example, cocoa butter and polyethylene glycol.
[0653] Another formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art
(see, e.g., U.S. Pat. No. 5,023,252, incorporated herein by
reference). Such patches may be constructed for continuous,
pulsatile, or on demand delivery of pharmaceutical agents.
[0654] It may be desirable or necessary to introduce the
pharmaceutical composition to the patient via a mechanical delivery
device. The construction and use of mechanical delivery devices for
the delivery of pharmaceutical agents is well known in the art.
Direct techniques for, for example, administering a drug directly
to the brain usually involve placement of a drug delivery catheter
into the patient's ventricular system to bypass the blood-brain
barrier. One such implantable delivery system, used for the
transport of agents to specific anatomical regions of the body, is
described in U.S. Pat. No. 5,011,472.
[0655] The compositions of the invention may also contain other
conventional pharmaceutically acceptable compounding ingredients,
generally referred to as carriers or diluents, as necessary or
desired. Any of the compositions of this invention may be preserved
by the addition of an antioxidant such as ascorbic acid or by other
suitable preservatives. Conventional procedures for preparing such
compositions in appropriate dosage forms can be utilized.
EXAMPLE 390
[0656]
22 A capsule formula is prepared from A compound of Formula I 40 mg
Starch 109 mg Magnesium stearate 1 mg
[0657] The components are blended, passed through an appropriate
mesh sieve, and filled into hard gelatin capsules.
EXAMPLE 391
[0658]
23 A tablet is prepared from A compound of Formula I 25 mg
Cellulose, microcrystalline 200 mg Colloidal silicon dioxide 10 mg
Stearic acid 5.0 mg
[0659] The ingredients are mixed and compressed to form
tablets.
[0660] The compound of this invention may be administered as the
sole pharmaceutical agent or in combination with one or more other
pharmaceutical agents where the combination causes no unacceptable
adverse effects. For example, the compounds of this invention may
be combined with known antiobesity or other indication agents, and
the like, as well as with admixtures and combinations thereof.
[0661] The compounds of Formula I may also be utilized, in free
base form or in compositions, in research and diagnostics, or as
analytical references standards, and the like. Therefore, the
present invention includes compositions which are comprised of an
inert carrier and an effective amount of a compound of Formula I,
or a salt or ester thereof. An inert carrier is any material which
does not interact with the compound to be carried and which lends
support, means of conveyance, bulk, traceable material, and the
like, to the compound to be carried. An effective amount of
compound is that amount which produces a result or exerts an
influence on the particular procedure being performed.
[0662] It should be apparent to one of ordinary skill in the art
that changes and modifications can be made to this invention
without departing from the spirit or scope of the invention as it
is set froth herein.
* * * * *