U.S. patent application number 12/229089 was filed with the patent office on 2010-02-25 for novel inhibitors of chymase.
Invention is credited to Lawrence de Garavilla, Michael N. Greco, Michael J. Hawkins, Bruce E. Maryanoff, Eugene Powell.
Application Number | 20100048513 12/229089 |
Document ID | / |
Family ID | 41696950 |
Filed Date | 2010-02-25 |
United States Patent
Application |
20100048513 |
Kind Code |
A1 |
Hawkins; Michael J. ; et
al. |
February 25, 2010 |
Novel inhibitors of chymase
Abstract
The present invention is directed to a compound of formula (I),
##STR00001## methods for preparing these compounds, compositions,
intermediates and derivatives thereof, and methods for treating
inflammatory and serine protease mediated disorders.
Inventors: |
Hawkins; Michael J.;
(Ambler, PA) ; Greco; Michael N.; (Lansdale,
PA) ; Powell; Eugene; (Pipersville, PA) ;
Garavilla; Lawrence de; (Downingtown, PA) ;
Maryanoff; Bruce E.; (Forest Grove, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
41696950 |
Appl. No.: |
12/229089 |
Filed: |
August 20, 2008 |
Current U.S.
Class: |
514/110 ;
514/119; 514/337; 514/354; 514/443 |
Current CPC
Class: |
A61K 31/445 20130101;
A61K 31/4535 20130101; A61K 31/662 20130101; A61P 11/06 20180101;
A61K 31/381 20130101; A61P 11/00 20180101 |
Class at
Publication: |
514/110 ;
514/443; 514/354; 514/337; 514/119 |
International
Class: |
A61K 31/381 20060101
A61K031/381; A61K 31/445 20060101 A61K031/445; A61K 31/4535
20060101 A61K031/4535; A61K 31/662 20060101 A61K031/662; A61P 11/00
20060101 A61P011/00 |
Claims
1. A method for treating or ameliorating a chymase mediated
disorder in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of a compound of
Formula (I): ##STR00136## wherein R.sup.1 is selected from the
group consisting of hydrogen and C.sub.1-4alkyl; ##STR00137## is
selected from the group consisting of aryl, heteroaryl, benzo fused
heterocyclyl, and cyclopropyl when n is 0 and one of R.sup.2 or
R.sup.3 is phenyl, and benzo fused cycloalkyl, and ring A is
optionally substituted with R.sup.2 and R.sup.3; R.sup.2 is one to
two substituents independently selected from the group consisting
of C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, methoxy,
C.sub.2-6alkoxy, C.sub.1-6alkylthio, --OCF.sub.3, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, and nitro; furthermore,
R.sup.2 is optionally oxo when ring A is heteroaryl or benzo fused
heterocyclyl; and, wherein any aryl-containing substituent of
R.sup.2 is optionally substituted with a substituent independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.2-6 alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, and nitro; and, wherein
any of the foregoing C.sub.1-6alkyl or C.sub.2-6 alkoxy containing
substituents of R.sup.2 are optionally substituted with a
substituent independently selected from the group consisting of
--NR.sup.11R.sup.12, aryl, heteroaryl, one to three halogens and
hydroxy; wherein R.sup.11 and R.sup.12 are independently hydrogen;
C.sub.1-6 alkyl optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, or --NR.sup.15R.sup.16; or aryl;
R.sup.15 and R.sup.16 are substituents independently selected from
the group consisting of hydrogen, C.sub.1-6 alkyl, and aryl, and
said R.sup.15 and R.sup.16 are optionally taken together with the
atoms to which they are attached to form a ring of five to seven
members; R.sup.3 is one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio, --OCF.sub.3, --OCH.sub.2(C.sub.2-6)alkenyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
--NHC(.dbd.O)Cy, --N(C.sub.1-6alkyl)C(.dbd.O)Cy,
--(NC(.dbd.O)).sub.2NH.sub.2, --C(.dbd.O)C.sub.1-4alkoxy,
--C(.dbd.O)NR.sup.17R.sup.18, --C(.dbd.O)NHcycloalkyl,
--C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl, --C(.dbd.O)NHCy,
--C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O)Cy,
--OC(.dbd.O)C.sub.1-6alkyl, --OC(.dbd.O)NR.sup.19R.sup.20,
--C(.dbd.O)Oaryl, --C(.dbd.O)Oheteroaryl, --CO.sub.2H, ureido,
halogen, hydroxy, nitro, cyano, aryl, heteroaryl, heteroaryloxy,
and aryloxy; wherein any of the foregoing C.sub.1-6alkyl or
C.sub.1-6 alkoxy containing substituents of R.sup.3 are optionally
substituted with one to three substituents independently selected
from the group consisting of --NR.sup.21R.sup.22, --NH(cycloalkyl),
--N(C.sub.1-6alkyl)(cycloalkyl), --NHCy, --N(C.sub.1-6alkyl)Cy,
aryl, heteroaryl, hydroxy, halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.O)C.sub.1-4alkoxy, and
--C(.dbd.O)Cy; wherein said R.sup.17, R.sup.18, R.sup.19, R.sup.20,
R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25, R.sup.26 are
substituents independently selected from the group consisting of
hydrogen, C.sub.1-6 alkyl, and aryl, wherein C.sub.1-6 alkyl is
optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; and R.sup.17 and R.sup.18, R.sup.19 and
R.sup.20, R.sup.21 and R.sup.22, R.sup.23 and R.sup.24, and
R.sup.25 and R.sup.26 are optionally taken together with the atoms
to which they are attached to form a ring of five to seven members;
Cy is a heterocyclyl optionally substituted with a substituent
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkoxy,
C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-6)alkyl,
--C(.dbd.O)(C.sub.1-6)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl, and heterocyclyl; wherein the aryl portion of any
aryl-containing substituent of Cy is optionally substituted with
one to three substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
halogen, hydroxy, NH.sub.2, NH(C.sub.1-6alkyl), and
--N(C.sub.1-6)dialkyl; and wherein heterocyclyl is optionally
substituted with aryl, one to three halogen atoms, or one to three
oxo substituents; and heterocyclyl is optionally spiro-fused to
said Cy; and wherein the C.sub.1-6alkenyl and C.sub.1-6alkynyl
substituents of R.sup.3 are optionally substituted with aryl or
--C(.dbd.O)NR.sup.27R.sup.28; wherein said R.sup.27 and R.sup.23
are independently hydrogen; C.sub.1-6 alkyl optionally substituted
with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2,
NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; or aryl; and R.sup.27
and R.sup.28 are optionally taken together with the atoms to which
they are attached to form a ring of five to seven members; wherein
the aryl, heteroaryl, and cycloalkyl substituents of R.sup.3 are
optionally substituted with one to three substituents independently
selected from R.sup.14; wherein R.sup.14 is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6alkenyl,
C.sub.1-6alkylthio, --NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy,
halogen, hydroxy, or nitro; and any one of the foregoing
C.sub.1-6alkyl- or C.sub.1-6alkoxy-containing substituents of
R.sup.14 is optionally substituted on a terminal carbon atom with a
substituent selected from --NR.sup.29R.sup.30, aryl, heteroaryl,
one to three halogen atoms, or hydroxy; wherein R.sup.29 and
R.sup.30 are independently hydrogen; C.sub.1-6 alkyl optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, NH(C.sub.1-6alkyl), or --N(C.sub.1-16)dialkyl; or aryl;
and R.sup.29 and R.sup.30 are optionally taken together with the
atoms to which they are attached to form a ring of five to seven
members; n is 0 or 1; W is O or S; X is hydrogen or C.sub.1-3alkyl;
Y is independently selected from the group consisting of
C.sub.1-6alkyl substituted with --OSO.sub.2NH.sub.2 or hydroxy;
SO.sub.3H, CO.sub.2H, heteroaryl, --OC(.dbd.O)NH.sub.2, and
P(.dbd.O)OR.sup.5R.sup.6 provided that when Y is CO.sub.2H, A and Z
must both be bicyclic ring systems; R.sup.5 is selected from the
group consisting of hydrogen; C.sub.1-6alkyl optionally substituted
with NH.sub.2, --NH(C.sub.1-16)alkyl, --N(C.sub.1-6)dialkyl,
1,3-dioxolan-2-yl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkoxycarbonyloxy, C.sub.1-6alkylcarbonylthio,
(C.sub.1-6)alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, one
to three halogens, or hydroxy; and aryl optionally substituted with
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.2-6
alkenyl, --NH.sub.2, --NH(C.sub.1-16)alkyl, --N(C.sub.1-6)dialkyl,
aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or
nitro; alternatively, when R.sup.5 is C.sub.1-8alkoxy, R.sup.5 and
R.sup.6 are taken together with the atoms to which they are
attached to form a 5-8 membered monocyclic ring; provided that
R.sup.5 is other than C.sub.1-6alkyl substituted with
di(C.sub.1-6)alkylamino-carbonyl when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z-R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-6alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3, and Z-R.sup.4 is 5-chloro-benzothiophen-3-yl; R.sup.6 is
selected from the group consisting of C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.2-8alkenyl, heteroaryl, aryl, and hydroxy;
wherein C.sub.1-8alkyl, C.sub.1-8alkoxy, and C.sub.2-8alkenyl are
optionally substituted with a substituent selected from the group
consisting of C.sub.1-6alkoxy, aryl, heterocyclyl, heteroaryl,
NH.sub.2, --NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
C.sub.1-6alkyl-carbonyloxy, C.sub.1-6alkylcarbonylthio,
C.sub.1-6alkoxycarbonyloxy, (C.sub.1-6)alkylamino-carbonyl,
di(C.sub.1-6)alkylaminocarbonyl, one to three halogen atoms, and
hydroxy; and when R.sup.6 is C.sub.1-8alkyl, said C.sub.1-8alkyl is
optionally substituted with one to four additional halogen atoms
such that one to three halogen atoms are optionally chlorine and
one to seven of the halogen atoms are optionally fluorine; wherein
the heteroaryl and aryl substituents of R.sup.6 are optionally
substituted with a substituent independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6
alkenyl, C.sub.1-6alkylthio, --NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy,
halogen, hydroxy, and nitro; Z is a seven to fifteen membered
monocyclic or polycyclic ring system selected from the group
consisting aryl, heteroaryl, benzo fused heterocyclyl, or benzo
fused cycloalkyl; R.sup.4 is one to three substituents selected
from the group consisting of: H, C.sub.1-6alkyl, C.sub.1-6alkenyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, aryl(C.sub.1-6)alkyl,
aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo, and cyano;
wherein C.sub.1-6alkyl, C.sub.1-6alkenyl and C.sub.1-6alkoxy are
optionally substituted with --NR.sup.33R.sup.34, aryl, heteroaryl,
cycloalkyl, one to three halogen atoms, or hydroxy; and aryl and
heteroaryl are each optionally substituted with a substituent
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.2-6 alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, one to three halogen atoms, hydroxy, and
nitro; wherein said R.sup.31, R.sup.32, R.sup.33, and R.sup.34 are
substituents independently selected from the group consisting of
hydrogen, C.sub.1-6 alkyl, and aryl, wherein alkyl is optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; and
R.sup.31 with R.sup.32 and R.sup.33 with R.sup.34 are optionally
taken together with the atoms to which they are attached to form a
ring of five to seven members; and pharmaceutically acceptable
salts thereof.
2. The method of claim 1 wherein the disorder is selected from the
group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
3. The method of claim 2 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
4. The method of claim 2 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
5. The method of claim 2 wherein said kidney fibrosis is associated
with glomerulonephritis.
6. The method of claim 2 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
7. The method of claim 6 wherein the chymase mediated disorder is
asthma.
8. The method of claim 6 wherein the chymase mediated disorder is
allergic rhinitis.
9. The method of claim 6 wherein the chymase mediated disorder is
pulmonary fibrosis.
10. The method of claim 1 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
11. The method of claim 1 wherein Y is independently selected from
SO.sub.3H and P(.dbd.O)OR.sup.5R.sup.6.
12. The method of claim 11 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
13. The method of claim 12 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
14. The method of claim 12 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular-grafts.
15. The method of claim 12 wherein said kidney fibrosis is
associated with glomerulonephritis.
16. The method of claim 12 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
17. The method of claim 16 wherein the chymase mediated disorder is
asthma.
18. The method of claim 16 wherein the chymase mediated disorder is
allergic rhinitis.
19. The method of claim 16 wherein the chymase mediated disorder is
pulmonary fibrosis.
20. The method of claim 11 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
21. A method for treating or ameliorating a chymase mediated
disorder in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of a compound of
Formula (Ia): ##STR00138## wherein ##STR00139## is independently
selected from the group consisting of aryl, heteroaryl, and benzo
fused heterocyclyl, optionally substituted with R.sup.2 and
R.sup.3; R.sup.2 is one to three substituents independently
selected from the group consisting of C.sub.1-4alkyl, methoxy,
C.sub.2-6alkoxy, NH.sub.2, NH(C.sub.1-16alkyl),
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and
nitro; wherein C.sub.1-6alkyl and C.sub.2-6alkoxy are optionally
substituted with a substituent selected from the group consisting
of --NR.sup.11R.sup.12, aryl, heteroaryl, one to three halogens and
hydroxyl; wherein C.sub.1-4alkyl and C.sub.2-6 alkoxy substituents
of R.sup.2 are optionally substituted with a substituent
independently selected from the group consisting of
--NR.sup.11R.sup.12, aryl, heteroaryl, one to three halogens and
hydroxy; wherein R.sup.11 and R.sup.12 are substituents
independently selected from the group consisting of hydrogen,
C.sub.1-6 alkyl, and aryl; wherein C.sub.1-6alkyl substituent of
R.sup.11 or R.sup.12 is optionally substituted with substituent
selected from the group consisting of hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, and --NR.sup.15R.sup.16; wherein said
R.sup.15 and R.sup.16 are substituents independently selected from
the group consisting of hydrogen, C.sub.1-6 alkyl, and aryl, and
said R.sup.15 and R.sup.16 are optionally taken together with the
atoms to which they are attached to form a ring of five to seven
members; R.sup.3 is one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.1-6alkoxy, --OCH.sub.2(C.sub.2-6)alkenyl,
NH.sub.2, --NH(C.sub.1-6alkyl), --N(C.sub.1-6)dialkyl,
--NHC(.dbd.O)Cy, --N(C.sub.1-6alkyl)C(.dbd.O)Cy,
--C(.dbd.O)C.sub.1-4alkoxy, --C(.dbd.O)NR.sup.17R.sup.18,
--C(.dbd.O)NHcycloalkyl, --C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl,
--C(.dbd.O)NHCy, --C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O)Cy,
--OC(.dbd.O)NR.sup.19R.sup.20, halogen, hydroxy, nitro, cyano,
aryl, and aryloxy; wherein alkyl and alkoxy are optionally
substituted with one to three substituents independently selected
from the group consisting of --NR.sup.21R.sup.22, --NHcycloalkyl,
--N(C.sub.1-6alkyl)cycloalkyl, --NHCy, --N(C.sub.1-6alkyl)Cy, aryl,
heteroaryl, halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.O)(C.sub.1-4)alkoxy, and
--C(.dbd.O)Cy; wherein alkenyl is optionally substituted on a
terminal carbon with aryl and --C(.dbd.O)NR.sup.27R.sup.28; and,
wherein aryl and cycloalkyl are optionally substituted with one to
three substituents independently selected from R.sup.14; Cy is a
heterocyclyl optionally substituted with a substituent selected
from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkoxy,
C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-6)alkyl,
--C(.dbd.O)(C.sub.1-6)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl, and heterocyclyl; wherein aryl and the aryl
portion of the C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)aryl and
--SO.sub.2aryl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, hydroxy, NH.sub.2,
NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; and wherein
heterocyclyl is optionally substituted with aryl, one to three
halogen atoms, or one to three oxo substituents; and, wherein
heterocyclyl is optionally spiro-fused to said Cy; R.sup.5 is
selected from the group consisting of hydrogen; C.sub.1-3alkyl
optionally substituted with NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkoxycarbonyloxy, C.sub.1-6alkylcarbonylthio,
(C.sub.1-6)alkylaminocarbonyl, di(C.sub.1-6)alkylaminocarbonyl, one
to three halogens, or hydroxy; and aryl optionally substituted with
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.2-6
alkenyl, --NH.sub.2, --NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or
nitro; alternatively, when R.sup.6 is C.sub.1-8alkoxy, R.sup.5 and
R.sup.6 are taken together with the atoms to which they are
attached to form a 5-8 membered monocyclic ring; and provided that
R.sup.5 is other than C.sub.1-3alkyl substituted with
di(C.sub.1-6)alkylamino-carbonyl when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z-R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3, and Z-R.sup.4 is 5-chloro-benzothiophen-3-yl; R.sup.6 is
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-8alkoxy, heteroaryl, aryl, and hydroxy; wherein alkyl and
C.sub.1-8alkoxy are optionally substituted on a terminal carbon
atom with a substituent selected from C.sub.1-3alkoxy, aryl, or
hydroxy; and alkoxy is optionally substituted on a terminal carbon
with a substituent independently selected from the group consisting
of C.sub.1-6alkylcarbonyloxy, and di(C.sub.1-6)alkylaminocarbonyl;
and wherein heteroaryl and aryl are optionally substituted with one
to three substituents independently selected from the group
consisting of aryl, hydroxy, C.sub.1-6alkoxy, and halogen; n is 0
or 1; Z is a bicyclic aryl or bicyclic heteroaryl; R.sup.4 is one
to three substituents selected from the group consisting of H,
C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkoxy,
aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo, and cyano;
wherein the alkyl and alkoxy are optionally substituted with a
substituent independently selected from the group consisting of
--NR.sup.33R.sup.34, aryl, one to three halogen atoms, and hydroxy;
wherein the aryl is optionally substituted with a substituent
independently-selected from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, aryl, halogen, hydroxy, and nitro;
wherein said R.sup.31, R.sup.32, R.sup.33, and R.sup.34 are
substituents independently selected from the group consisting of
hydrogen, C.sub.1-6 alkyl, and aryl, wherein alkyl is optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; and
R.sup.31 with R.sup.32 and R.sup.33 with R.sup.34 are optionally
taken together with the atoms to which they are attached to form a
ring of five to seven members; and pharmaceutically acceptable
salts thereof.
22. The method of claim 21 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
23. The method of claim 22 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
24. The method of claim 22 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
25. The method of claim 22 wherein said kidney fibrosis is
associated with glomerulonephritis.
26. The method of claim 22 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
27. The method of claim 26 wherein the chymase mediated disorder is
asthma.
28. The method of claim 26 wherein the chymase mediated disorder is
allergic rhinitis.
29. The method of claim 26 wherein the chymase mediated disorder is
pulmonary fibrosis.
30. The method of claim 21 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
31. The method of claim 21 wherein, in the compound, R.sup.1, ring
A, R.sup.2, R.sup.3, R.sup.5, R.sup.6, Z, and R.sup.4 are
dependently selected from the group consisting of: TABLE-US-00032
##STR00140## R.sup.5 R.sup.6 n W Z-R.sup.4 naphthalen-2-yl H
CH.sub.3 0 O 5-Cl-N-methyl- indol-3-yl 3,4-difluoro-phenyl H OH 1 O
5-Cl- benzothiophen-3-yl naphthalen-2-yl H OH 0 O
5-Cl-N-methyl-indol-3-yl 4-fluoro-phenyl H OH 1 O
5-Cl-N-methyl-indol-3-yl naphthalen-2-yl H OH 0 O 5-Me-
benzothiophen-2-yl 3-fluoro-phenyl H CH.sub.3 1 O
5-Cl-N-methyl-indol-3-yl 3,4-difluoro-phenyl H CH.sub.3 1 O
5-Cl-N-methyl-indol-3-yl 4-{[1-(naphthalen-2- H OH 0 O
naphthalen-1-yl ylcarbonyl)-piperadin-4- ylcarbonyl]-
amino}naphthalen-2-yl naphthalen-2-yl H OH 0 O
5-Cl-benzothiophen-3-yl naphthalen-2-yl H OH 0 O
5-F-benzothiophen-3-yl naphthalen-2-yl H OH 0 O
5-F-N-methyl-indol-3-yl 4-amino-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl naphthalen-2-yl H OH 0 O
5-Br-N-methyl-indol-3-yl Phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-fluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3,4-trifluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3,4-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl H OH 1 O 5-Cl-benzothiophen-2-yl
4-fluoro-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl naphthalen-2-yl H
CH.sub.3 0 O 5-Cl-benzothiophen-3-yl 2-fluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl naphthalen-2-yl H OH 0 O
N-methyl-indol-3-yl naphthalen-2-yl H OH 0 O
5-Br-benzothiophen-3-yl 4-fluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl pyridin-3-yl H OH 1 O
5-Cl-benzothiophen-3-yl naphthalen-2-yl H OH 0 O benzothiophen-3-yl
naphthalen-2-yl H OH 0 O N-(3-phenyl-allyl)-indol-3-yl
naphthalen-2-yl H CH.sub.2CH.sub.3 0 O 5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl H CH.sub.2CH.sub.3 1 O 5-Cl-benzothiophen-3-yl
benzothiazol-6-yl H OH 0 O 5-Cl-benzothiophen-3-yl naphthalen-2-yl
H OH 0 O naphthalen-1-yl naphthalen-2-yl H CH.sub.3 0 O
2-(4-phenyl-piperidin-1- ylcarbonyl)-benzothiophen-3-yl
naphthalen-2-yl H CH.sub.3 0 O naphthalen-1-yl naphthalen-2-yl H
3-methoxy- 0 O 5-Cl-benzothiophen-3-yl propyl naphthalen-2-yl H
CH.sub.3 0 O 2-(4-(4-methoxyphenyl)- piperidin-1-ylcarbonyl)-
benzothiophen-3-yl naphthalen-2-yl H Phenethyl 0 O
5-Cl-benzothiophen-3-yl phenyl H OH 1 O naphthalen-1-yl
4-methoxy-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl naphthalen-2-yl H
3-(Benzo 0 O 5-Cl-benzothiophen-3-yl [1,3]dioxol-5- yl)-propyl
naphthalen-2-yl H 3-(naphthyl 0 O 5-Cl-benzothiophen-3-yl en-1yl)
propyl naphthalen-2-yl H CH.sub.3 0 O 2-(4-Benzyloxycarbonyl)-
piperazin-1-ylcarbonyl))- -benzothiophen-3-yl 4-methyl-phenyl H OH
1 O 5-Cl-benzothiophen-2-yl naphthalen-2-yl H 3- 0 O
5-Cl-benzothiophen-3-yl (4-hydroxy 0 O phenyl) propyl
3-((N-Benzoyl-piperidin-4- H OH 0 O naphthalen-1-yl
ylamino)-methyl)- naphthalen-2-yl naphthalen-2-yl H OH 0 S
5-Cl-benzothiophen-3-yl 3-[(4-phenyl-cyclohex-3- H OH 0 O
naphthalen-1-yl enyl)-N-methyl- aminocarbonyl]-naphthalen- 2-yl
naphthalen-2-yl H CH.sub.3 0 O 2-((4-F-phenyl)-piperidin-1-
ylcarbonyl)-benzothiophen-3-yl naphthalen-2-yl H (3-phenyl) 0 O
5-Cl-benzothiphen-3-yl propyl 3,4-dimethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl naphthalen-2-yl H (4-phenyl) 0 O
5-Cl-benzothiphen-3-yl butyl naphthalen-2-yl H OH 0 O
6-Cl-N-methyl-indol-3-yl naphthalen-2-yl H 3-(4-methoxy 0 O
5-Cl-benzothiphen-3-yl phenyl) propyl 3-[4-((3-Phenethyl)- H OH 0 O
naphthalen-1-yl pyrrolidin-1-ylcarbonyl)]- naphthalen-2-yl
benzothiophen-5-yl H OH 0 O 5-Cl-benzothiophen-3-yl naphthalen-2-yl
H OH 0 O 5-carboxy-N-Me-indol-3-yl- quinolin-3-yl H OH 0 O
naphthalen-1-yl naphthalen-2-yl H OH 0 O 7-Cl-N-methyl-indol-3-yl
benzo[b]thiophen-6-yl H OH 0 O naphthalen-1-yl
3-[4-(6-Chloro-2-oxo-2,3- H OH 0 O naphthalen-1-yl
dihydro-benzoimidazol-1- yl)-piperidin-1-ylcarbonyl]-
naphthalen-2-yl 4-biphenyl H OH 0 O naphthalen-1-yl naphthalen-2-yl
H OH 0 O N-cyclopropyl methyl-indol-3-yl naphthalen-2-yl H OH 0 O
4-Cl-N-methyl-indol-3-yl benzothiophen-2-yl H OH 0 O
naphthalen-1-yl naphthalen-2-yl H OH 0 O
5-cyano-N-methyl-indol-3-yl 4-hydroxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl (6-Br)-naphthalen-2-yl H OH 0 O
5-Cl-benzothiophen-3-yl naphthalen-2-yl H OH 0 O Indol-3-yl
2-Amino- H OH 0 O 5-Cl-benzothiophen-3-yl benzothiazol-5-yl
3-(Cyclohexylamino) H OH 0 O naphthalen-1-yl methyl-naphthalen-2-yl
naphthalen-2-yl H OH 0 O 5-Ph-benzothiophen-3-yl 3-(N-benzyl- H OH
0 O naphthalen-1-yl aminocarbonyloxy methyl) naphthalen-2-yl
3-(pyridin-4-yl-pyrrolidin-1- H OH 0 O naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl naphthalen-2-yl H OH 0 O
5-methoxy-N-methyl- indol-3-yl 3-(methoxycarbonyl)- H OH 0 O
naphthalen-1-yl naphthalen-2-yl naphthalen-2-yl H OH 0 O
6-Br-benzothiophen-3-yl naphthalen-2-yl H OH 0 O
N-isopropyl-indol-3-yl 4-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl quinolin-6-yl H OH 0 O naphthalen-1-yl
4-trifluoromethyl-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl
naphthalen-2-yl H OH 0 O N-phenyl-indol-3-yl
(4-(1H-indol-3-yl)-piperidin- H OH 0 O naphthalen-1-yl
1-ylcarbonyl)-naphthalen-2- yl Indanyl H OH 0 O naphthalen-1-yl
naphthalen-2-yl H OH 0 O 5-Cl-1,1-dioxo-benzothiophen- 3-yl
((3-phenyl)pyrrolidin-1- H OH 0 O naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl naphthalen-2-yl H Ph 0 O
5-Cl-benzothiophen-3-yl ((3-Methyl)- H OH 0 O naphthalen-1-yl
cyclohexylamino)methyl- naphthalen-2-yl 3-(cyclopentyl-N- H OH 0 O
naphthalen-1-yl methylamino-carbonyl)- naphthalen-2-yl
3-((5-methoxy H OH 0 O naphthalen-1-yl carbonyl)aminomethyl)-
naphthalen-2-yl 3-(4-(2-oxo-2,3-dihydro- H OH 0 O naphthalen-1-yl
benzoimidazol-1-yl)- piperidin-1-ylcarbonyl)- naphthalen-2-yl
3-(phenyl- H OH 0 O naphthalen-1-yl aminocarbonyloxy)-methyl)-
naphthalen-2-yl 3-(N-phenyl-carbamoyloxy)- H OH 0 O naphthalen-1-yl
naphthalen-2-yl quinolin-2-yl H OH 0 O naphthalen-1-yl
3-((4-Phenoxy-phenyl)- H OH 0 O naphthalen-1-yl aminocarbonyloxy
methyl)- naphthalen-2-yl naphthalen-2-yl H OH 0 O
5-(4-F-phenyl)-N-methyl-indol- 3-yl naphthalen-2-yl H OH 0 O
4-Br-benzo thiophen-3-yl 3-[(4-Benzotriazol-1-yl- H OH 0 O
naphthalen-1-yl piperidin-1-ylcarbonyl)]- naphthalen-2-yl
3-(4-phenyl)-piperidin-1- H OH 0 O naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl 3-((naphthalen-2- H OH 0 O
naphthalen-1-yl ylcarbonyl)-piperidin-4- ylmethylamino-methyl)-
naphthalen-2-yl 3-((3-Benzenesulfonyl)- H OH 0 O naphthalen-1-yl
pyrrolidin-1-ylcarbonyl)- naphthalen-2-yl 3-(N-[3-(4-Oxo-1-phenyl-
H OH 0 O naphthalen-1-yl 1,3,8-triaza-spiro[4.5]
decane-8-carbonyl)- naphthalen-2-yl 3-(naphthalen-2- H OH 0 O
naphthalen-1-yl ylaminocarbonyloxy- methyl)-naphthalen-2-yl
2-fluorenyl H OH 0 O naphthalen-1-yl 3-(Benzylaminomethyl)- H OH 0
O naphthalen-1-yl naphthalen-2-yl (3-OH)naphthalen-2-yl H OH 0 O
naphthalen-1-yl 3-(N-Benzyl-3- H OH 0 O naphthalen-1-yl
acrylamide)naphthalen-2-yl 3-((5-Phenyl)-pentylamino)- H OH 0 O
naphthalen-1-yl naphthalen-2-yl 3-(N-Benzyl-N-methyl- H OH 0 O
naphthalen-1-yl aminocarbonyl)-naphthalen- 2-yl 3-[(5H- H OH 0 O
naphthalen-1-yl Dibenzo[a,d]cyclohepten-5-
yl)-propyl]-methyl-amino- methyl-naphthalen-2-yl
3-(4-(Benzothiazol-2-yl- H OH 0 O naphthalen-1-yl
piperidin-1-ylcarbonyl))- naphthalen-2-yl 1-(2-Oxo-2-(4-phenyl- H
OH 0 O naphthalen-1-yl piperidin-1-yl)-ethoxy)- naphthalen-2-yl
3-([2-(3,4-dimethoxy- H OH 0 O naphthalen-1-yl
phenyl)-ethyl]-N-methyl- aminocarbonyl)- naphthalen-2-yl
naphthalen-2-yl H OH 0 O 1-Me-1H-pyrrolo[2,3-b]pyridine
3-((4-OH-cyclohexylamino)- H OH 0 O naphthalen-1-yl
methyl)-naphthalen-2-yl naphthalen-2-yl H CH.sub.3 0 O 2-carboxy-
benzothiophen-3-yl 3-(Benzyl H OH 0 O naphthalen-1-yl
aminocarbonyl)-naphthalen- 2-yl 3-(3-Phenyl-allyloxy)- H OH 0 O
naphthalen-1-yl naphthalen-2-yl 3-(Benzyloxy)- H OH 0 O
naphthalen-1-yl naphthalen-2-yl 3-(methoxycarbonyl- H OH 0 O
naphthalen-1-yl methoxy)-nephthalen-2-yl 3-(Cyclopentylamino- H OH
0 O naphthalen-1-yl methyl)-nephthalen-2-yl naphthalen-2-yl H OH 0
O 5-Cl-benzothiphen-23-yl 3-(Phenethyl- H OH 0 O naphthalen-1-yl
methylaminomethyl) naphthalen-2-yl naphthalen-2-yl H CH.sub.3 0 O
2-(benzylaminocarbonyl)- benzothiophen-3-yl naphthalen-2-yl H OH 0
O N-phenyl-indol-4-yl Indol-5-yl H OH 0 O naphthalen-1-yl
3-(3-Phenyl- H OH 0 O naphthalen-1-yl propylcarbamoyl)-methoxy)-
naphthalen-2-yl 3-(2-phenyl-pyrrolidin-1- H OH 0 O naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl 3-amino-naphthalen-2-yl H OH 0 O
naphthalen-1-yl 3-((5-hydroxypentylamino)- H OH 0 O naphthalen-1-yl
methyl)-naphthalen-2-yl 1-(methoxycarbonyl- H OH 0 O
naphthalen-1-yl methoxy)-naphthalen-2-yl benzo[1,3]dioxolyl H OH 0
O naphthalen-1-yl isoquinolin-3-yl H OH 0 O naphthalen-1-yl
3-phenoxy-phenyl H OH 0 O naphthalen-1-yl 3-(isopropyloxycarbonyl)-
H OH 0 O naphthalen-1-yl naphthalen-2-yl naphthalen-2-yl H OH 0 O
benzothiophen-2-yl 3-{[1-(naphthalen-2- H OH 0 O naphthalen-1-yl
ylcarbonyl)-piperidin-4- ylcarbonyl]-amino}-
naphthalen-2-yl 3-(benzylmethyl H OH 0 O naphthalen-1-yl
aminomethyl)- naphthalen-2-yl naphthalen-2-yl H OH 0 O
6-(4-butylphenyl)- benzothiophen-3-yl trans-2-phenylcycloprop-1- H
CH.sub.3 0 O 5-Cl-benzothiophen-3-yl yl 2-methoxy-phenyl H CH.sub.3
1 O 5-Cl-benzothiophen-3-yl benzofuran-2-yl H CH.sub.3 0 O
5-Cl-benzothiophen-3-yl 2-nitro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-methylcarbonyloxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-hydroxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl pyridin-2-yl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-amino-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-trifluoromethyl-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-trifluoromethoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-methoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-methyl-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 4-cyano-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-ureido-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-(NHC(.dbd.O)).sub.2NH.sub.2-phenyl H
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 2-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-bromo-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2,3-dimethoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiphen-3-yl 3-nitro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-bromo-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3,5-dimethoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2,5-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3,5-dichloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2,4-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-amino-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl --CH.sub.2C(Me).sub.2CH.sub.2O-- 1 O
naphthalen-1-yl phenyl 3-methoxy- OH 1 O naphthalen-1-yl prop-1-yl
phenyl 3-methoxy- 3-methoxy- 1 O naphthalen-1-yl prop-1-yl
prop-1-yl-oxy phenyl 2-(1,3- OH 1 O naphthalen-1-yl dioxolan-2-yl)-
eth-1-yl phenyl --CH.sub.2OC(.dbd.O) OH 1 O naphthalen-1-yl t-butyl
phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O naphthalen-1-yl phenyl
(2-dimethyl 2-dimethyl 1 O naphthalen-1-yl amino)- amino-ethoxy
eth-1-yl phenyl --CH.sub.2C(.dbd.O) --OCH.sub.2 1 O naphthalen-1-yl
NEt.sub.2 C(.dbd.O) NEt.sub.2 phenyl --(CH.sub.2).sub.2S
--O(CH.sub.2).sub.2S 1 O naphthalen-1-yl C(.dbd.O) C(.dbd.O)
t-butyl t-butyl 3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1
O 5-Cl-benzothiophen-3-yl t-butyl 3,4-difluoro-phenyl (2-dimethyl
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl amino)- 1 O
5-Cl-benzothiphen-3-yl eth-1-yl 3,4-difluoro-phenyl (2-amino)-
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl eth-1-yl 3,4-difluoro-phenyl
--CH.sub.2C(.dbd.O) CH.sub.3 1 O 5-Cl-bezothiophen-3-yl NEt.sub.2
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 3,4-difluoro-phenyl
--CH.sub.2C(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
NEt.sub.2 C(.dbd.O) NEt.sub.2 3,4-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl methyl 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
2-methoxy-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl pyridin-2-yl H OH
1 O 5-Cl-benzothiophen-3-yl 3-trifluromethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-methoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3,5-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2-bromo-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2,3-dimethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-nitro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-bromo-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3,5-dimethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2,5-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3,5-dichloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2,4-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-amino-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2-methoxy-phenyl --CH.sub.2OC(.dbd.) t-
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl pyridin-2-yl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
3-trifluoromethoxy-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 3-methoxy-phenyl --CH.sub.2OC(.dbd.O)
t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl 2,6-difluoro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
2-chloro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 3-chloro-phenyl --CH.sub.2OC(.dbd.O)
t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 2-bromo-phenyl --CH.sub.2OC(.dbd.O)
t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl 2,3-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
3-nitro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 3-bromo-phenyl --CH.sub.2OC(.dbd.O)
t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl 3,5-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 3,5-dichloro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 3-amino-phenyl --CH.sub.2OC(.dbd.O)
t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl 2-methoxy-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl pyridin-2-yl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
3-trifluoromethoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 3-methoxy-phenyl
--CH.sub.2OC(.dbd.) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl
OC(.dbd.O) t-butyl 2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.) t-butyl
2-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 3-chloro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.) t-butyl 3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 2-bromo-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 2,3-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 3-nitro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
3-bromo-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 3-amino-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl'
t-butyl OC(.dbd.O) t-butyl 2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH
1 O 5-Cl-benzothiophen-3-yl t-butyl pyridin-2-yl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen--3yl t-butyl
3-trifluoromethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 2,3-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
2-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 3-nitro-phenyl --CH.sub.2OC(.dbd.O)
OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
3-bromo-phenyl --CH.sub.2OC(.dbd.O) H 1 O 5-Cl-benzothiphen-3-yl
t-butyl 3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 2,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiphen-3-yl t-butyl
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
3-amino-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 2-methoxy-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl pyridin-2-yl --CH.sub.2CH.sub.2CH.sub.2O--
1 O 5-Cl-benzothiophen-3-yl 3-trifluoromethoxy-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3-methoxy-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2,6-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
2-chloro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 3-chloro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3,5-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2,3-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
2-bromo-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2,3-dimethoxy-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3-nitro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 3-bromo-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3,5-dimethoxy-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2,5-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3,5-dichloro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2,4-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3-amino-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1
O 5-Cl-benzothiophen-3-yl isopropyloxy pyridin-2-yl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
3-trifluoromethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
isopropyloxy 3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 2,3-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
2-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
isopropyloxy 2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isoproyloxy
3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
isopropyloxy 3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophne-3-yl isopropyloxy 2,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
3-amino-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
isopropyloxy 3-fluoro-5-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-fluoro-3-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 4-fluoro-3-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-fluoro-5-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3,5-dibromo-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-cyano-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 2-cyano-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 3-fluoro-5-trifluoromethyl- H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl 3-fluoro-5-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2-fluoro-3-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 4-fluoro-3-chloro-phenyl H OH 1 O
5-Cl-benzothiophne-3-yl 2-fluoro-5-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3,5-dibromo-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-cyano-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 2-cyano-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3-fluoro-5-trifluoromethyl- H OH 1 O
5-Cl-benzothiophne-3-yl phenyl 3-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
2-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 4-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
2-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 3,5-dibromo-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
3-cyano-pheyl --CH.sub.2OC(.dbd.O) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl butyl 2-cyano-phenyl --CH.sub.2OC(.dbd.O)
t- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl butyl
3-fluoro-5-trifluoromethyl- --CH.sub.2OC(.dbd.) t- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl butyl 3-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 2-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 4-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 2-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
3-cyano-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 2-cyano-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 3-fluoro-5-trifluoromethyl-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl OC(.dbd.O) t-butyl 3-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
2-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 4-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
2-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 3,5-dibromo-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl
3-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 2-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 3-fluoro-5-trifluoromethyl-
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl phenyl t-butyl
3-fluoro-5-chloro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2-fluoro-3-chloro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
4-fluoro-3-chloro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 2-fluoro-5-chloro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
3,5-dibromo-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 3-cyano-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
2-cyano-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 3-fluoro-5-trifluoromethyl-
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl phenyl
3-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 2-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
4-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 2-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
2-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
isopropyloxy and 3-fluoro-5-trifluoromethyl- --CH.sub.2OC(.dbd.O)
OH 1 O 5-Cl-benzothiophen-3-yl phenyl isopropyloxy
32. The method of claim 31 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
33. The method of claim 32 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
34. The method of claim 32 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
35. The method of claim 32 wherein said kidney fibrosis is
associated with glomerulonephritis.
36. The method of claim 32 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
37. The method of claim 36 wherein the chymase mediated disorder is
asthma.
38. The method of claim 36 wherein the chymase mediated disorder is
allergic rhinitis.
39. The method of claim 36 wherein the chymase mediated disorder is
pulmonary fibrosis.
40. The method of claim 1 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
41. The method of claim 31 wherein the compounds have a formula
selected from the group consisting of: ##STR00141## ##STR00142##
##STR00143## ##STR00144## ##STR00145## ##STR00146##
##STR00147##
47. The method of claim 46 wherein the chymase mediated disorder is
asthma.
48. The method of claim 46 wherein the chymase mediated disorder is
allergic rhinitis.
49. The method of claim 46 wherein the chymase mediated disorder is
pulmonary fibrosis.
50. The method of claim 41 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
51. The method of claim 41 wherein the compound is selected from
the group consisting of: ##STR00148##
42. The method of claim 41 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
43. The method of claim 42 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
44. The method of claim 42 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
45. The method of claim 42 wherein said kidney fibrosis is
associated with glomerulonephritis.
46. The method of claim 42 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury. ##STR00149##
##STR00150## ##STR00151## ##STR00152## ##STR00153##
##STR00154##
52. The method of claim 51 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
53. The method of claim 52 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
54. The method of claim 52 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
55. The method of claim 52 wherein said kidney fibrosis is
associated with glomerulonephritis.
56. The method of claim 52 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
57. The method of claim 56 wherein the chymase mediated disorder is
asthma.
58. The method of claim 56 wherein the chymase mediated disorder is
allergic rhinitis.
59. The method of claim 56 wherein the chymase mediated disorder is
pulmonary fibrosis.
60. The method of claim 51 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
61. A method for treating or ameliorating a chymase mediated
disorder in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of a compound of
Formula Ia selected from the group consisting of: TABLE-US-00033
(Ia) ##STR00155## Cpd ##STR00156## R.sup.5 R.sup.6 n W Z-R.sup.4 2
3,4-difluoro-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl 17
3,4-difluoro-phenyl H CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 170
3,5-dichloro-phenyl H CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 187
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 191 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
207 3,5-dichloro-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl 261
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 297 3,5-dichloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
isopropyloxy.
62. The method of claim 61 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
63. The method of claim 62 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
64. The method of claim 62 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
65. The method of claim 62 wherein said kidney fibrosis is
associated with glomerulonephritis.
66. The method of claim 62 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
67. The method of claim 66 wherein the chymase mediated disorder is
asthma.
68. The method of claim 66 wherein the chymase mediated disorder is
allergic rhinitis.
69. The method of claim 66 wherein the chymase mediated disorder is
pulmonary fibrosis.
70. The method of claim 61 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
71. A method of claim 61 wherein the compound is: ##STR00157##
72. The method of claim 71 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
73. The method of claim 72 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
74. The method of claim 72 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
75. The method of claim 72 wherein said kidney fibrosis is
associated with glomerulonephritis.
76. The method of claim 72 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
77. The method of claim 76 wherein the chymase mediated disorder is
asthma.
78. The method of claim 76 wherein the chymase mediated disorder is
allergic rhinitis.
79. The method of claim 76 wherein the chymase mediated disorder is
pulmonary fibrosis.
80. The method of claim 71 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
81. A method of claim 61 wherein the compound is: ##STR00158##
82. The method of claim 81 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
83. The method of claim 82 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
84. The method of claim 82 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
85. The method of claim 82 wherein said kidney fibrosis is
associated with glomerulonephritis.
86. The method of claim 82 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
87. The method of claim 86 wherein the chymase mediated disorder is
asthma.
88. The method of claim 86 wherein the chymase mediated disorder is
allergic rhinitis.
89. The method of claim 86 wherein the chymase mediated disorder is
pulmonary fibrosis.
90. The method of claim 81 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
91. A method of claim 61 wherein the compound is: ##STR00159##
92. The method of claim 91 wherein the disorder is selected from
the group consisting of allergic rhinitis, viral rhinitis, asthma,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, acute lung injury, psoriasis, arthritis, reperfusion
injury, ischemia, hypertension, hypercardia, myocardial infarction,
heart failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis, pulmonary fibrosis, kidney fibrosis, liver fibrosis,
post surgical adhesion formation, systemic sclerosis, keloid scars,
rheumatoid arthritis, bullous pemphigiod and atherosclerosis.
93. The method of claim 92 wherein said acute lung injury is adult
(acute) respiratory distress syndrome.
94. The method of claim 92 wherein said vascular stenosis or
restenosis is associated with vascular injury, angioplasty,
vascular stents or vascular grafts.
95. The method of claim 92 wherein said kidney fibrosis is
associated with glomerulonephritis.
96. The method of claim 92 wherein the chymase mediated disorder is
selected from the group consisting of asthma, allergic rhinitis,
chronic obstructive pulmonary disease, bronchitis, pulmonary
emphysema, pulmonary fibrosis, and acute lung injury.
97. The method of claim 96 wherein the chymase mediated disorder is
asthma.
98. The method of claim 96 wherein the chymase mediated disorder is
allergic rhinitis.
99. The method of claim 96 wherein the chymase mediated disorder is
pulmonary fibrosis.
100. The method of claim 91 wherein the therapeutically effective
amount of the compound of claim 1 is from about 0.001 mg/kg/day to
about 1000 mg/kg/day.
Description
[0001] This application claims priority from application Ser. No.
11/037,938, filed Jan. 18, 2005, which claims priority from
application Ser. No. 60/538,663, filed Jan. 23, 2004, which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to certain novel compounds,
methods for preparing compounds, compositions, intermediates and
derivatives thereof and methods for treating inflammatory and
serine protease mediated disorders. More particularly, the
compounds of the present invention are serine protease inhibitors
useful for treating inflammatory and serine protease mediated
disorders.
BACKGROUND OF THE INVENTION
[0003] Serine proteases represent a broad class of proteolytic
enzymes that are involved; in physiological processes such as blood
coagulation, complement activation, phagocytosis and turnover of
damaged cell tissue. Human chymase (EC.3.4.21.39) is a glycosylated
monomeric chymotrypsin-like serine protease (MW=30 kDa) localized
mainly in mast cell secretory granules. Chymase is thought to have
a variety of functions, including degradation of extracellular
matrix proteins, cleavage of angiotensin I to angiotensin II
(except in the rat), and activation of matrix proteases and
cytokines. Endogenously, chymase is regulated by the serpins
.alpha.1-antichymotrypsin and .alpha.1-proteinase.
[0004] Although the precise patho-physiological roles of chymase
have yet to be determined, chymase has been implicated in
microvascular leakage, neutrophil accumulation, the stimulation of
mucus secretion, and the modulation of cytokines. A potent,
chymase-selective inhibitor may be indicated in mast cell-mediated
diseases such as asthma, pulmonary inflammation, and chronic
obstructive pulmonary diseases (COPD). Because chymase can play a
role in the generation of cardiac and vascular wall angiotensin II,
an inhibitor may have potential use as an antihypertensive
treatment for vascular wall injury and inflammation
(atherosclerosis/restenosis), as well as cardiac hypertrophy. Thus,
small molecule inhibitors of chymase are likely to represent useful
therapeutic agents.
[0005] U.S. Pat. No. 5,508,273 to Beers, et al. and Bioorganic
& Med. Chem. Lett., 1995, 5 (16), 1801-1806 describe phosphonic
acid compounds useful in treating bone wasting diseases. In
particular, 1-napthylmethylphosphonic acid derivatives have been
described as osteoclastic acid phosphatase inhibitors of the
formula:
##STR00002##
[0006] Accordingly, it is an object of the present invention to
provide phosphonic acid and phosphinic acid compounds that are
serine protease inhibitors, in particular, inhibitors of chymase,
useful for treating inflammatory and serine protease mediated
disorders. It is another object of the invention to provide a
process for preparing phosphonic or phosphinic acid compounds,
compositions, intermediates and derivatives thereof. It is a
further object of the invention to provide methods for treating
inflammatory and serine protease mediated disorders.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a compound of Formula
(I)
##STR00003##
wherein [0008] R.sup.1 is selected from the group consisting of
hydrogen and C.sub.1-4alkyl;
[0008] ##STR00004## is selected from the group consisting of aryl,
heteroaryl, benzo fused heterocyclyl, cyclopropyl when n is 0 and
one of R.sup.2 or R.sup.3 is phenyl, and benzo fused cycloalkyl,
and ring A is optionally substituted with R.sup.2 and R.sup.3;
[0009] R.sup.2 is one to two substituents independently selected
from the group consisting of C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, methoxy, C.sub.2-6alkoxy, C.sub.1-6alkylthio,
--OCF.sub.3, --NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy,
halogen, hydroxy, and nitro; furthermore, R.sup.2 is optionally oxo
when ring A is heteroaryl or benzo fused heterocyclyl; and, wherein
any aryl-containing substituent of R.sup.2 is optionally
substituted with a substituent independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6
alkenyl, C.sub.1-6alkylthio, --NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy,
halogen, hydroxy, and nitro; [0010] and, wherein any of the
foregoing C.sub.1-6alkyl or C.sub.2-6 alkoxy containing
substituents of R.sup.2 are optionally substituted with a
substituent independently selected from the group consisting of
--NR.sup.11R.sup.12, aryl, heteroaryl, one to three halogens and
hydroxy; wherein R.sup.11 and R.sup.12 are independently hydrogen;
C.sub.1-6 alkyl optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, or --NR.sup.15R.sup.16; or aryl; [0011]
R.sup.15 and R.sup.16 are substituents independently selected from
the group consisting of hydrogen, C.sub.1-6 alkyl, and aryl, and
said R.sup.15 and R.sup.16 are optionally taken together with the
atoms to which they are attached to form a ring of five to seven
members; [0012] R.sup.3 is one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkylthio, --OCF.sub.3, --OCH.sub.2(C.sub.2-6)alkenyl,
--NH.sub.2, --NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
--NHC(.dbd.O)Cy, --N(C.sub.1-6alkyl)C(.dbd.O)Cy,
--(NC(.dbd.O)).sub.2NH.sub.2, --C(.dbd.O)C.sub.4alkoxy;
--C(.dbd.O)NR.sup.17R.sup.18, --C(.dbd.O)NHcycloalkyl,
--C(.dbd.O)N(C alkylcycloalkyl, --C(.dbd.O)NHCy,
--C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O--)Cy,
--OC(.dbd.O)C.sub.1-6alkyl, --OC(.dbd.O)NR.sup.19R.sup.20,
--C(.dbd.O)Oaryl, --C(.dbd.O)Oheteroaryl, --CO.sub.2H, ureido,
halogen, hydro nitro, cyano, aryl, heteroaryl, heteroaryloxy, and
aryloxy; [0013] wherein any of the foregoing C.sub.1-6alkyl or
C.sub.1-6 alkoxy containing substituents of R.sup.3 are optionally
substituted with one to three substituents independently selected
from the group consisting of --NR.sup.21R.sup.22, --NH(cycloalkyl),
--N(C.sub.1-6alkyl)(cycloalkyl), --NHCy, --N(C.sub.1-6alkyl)Cy,
aryl, heteroaryl, hydroxy, halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.O)C.sub.1-4alkoxy, and
--C(.dbd.O)Cy; [0014] wherein said R.sup.17, R.sup.18, R.sup.19,
R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
R.sup.26 are substituents independently selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, and aryl, wherein
C.sub.1-6 alkyl is optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; and R.sup.17 and R.sup.13, R.sup.19 and
R.sup.20, R.sup.21 and R.sup.22, R.sup.23 and R.sup.24 and R.sup.25
and R.sup.26 are optionally taken together with the atoms to which
they are attached to form a ring of five to seven members; [0015]
Cy is a heterocyclyl optionally substituted with a substituent
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkyl,
--C.sub.1-6alkylC(.dbd.O)C.sub.1-6alkoxy,
C.sub.1-6alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-6)alkyl,
--C(.dbd.O)(C.sub.1-6)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl, and heterocyclyl; wherein the aryl portion of any
aryl-containing substituent of Cy is optionally substituted with
one to three substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6alkylthio,
halogen, hydroxy, NH.sub.2, NH(C.sub.1-6alkyl), and
--N(C.sub.1-6)dialkyl; and wherein heterocyclyl is optionally
substituted with aryl, one to three halogen atoms, or one to three
oxo substituents; and heterocyclyl is optionally spiro-fused to
said Cy; [0016] and wherein the C.sub.1-6alkenyl and
C.sub.1-6alkynyl substituents of R.sup.3 are optionally substituted
with aryl or --C(.dbd.O)NR.sup.27R.sup.28; wherein said R.sup.27
and R.sup.28 are independently hydrogen; C.sub.1-6 alkyl optionally
substituted with hydroxy, aryl, --C(.dbd.O)C.sub.1-4alkoxy,
NH.sub.2, NH(C.sub.1-6alkyl), or --N(C.sub.1-6)dialkyl; or aryl;
and R.sup.27 and R.sup.28 are optionally taken together with the
atoms to which they are attached to form a ring of five to seven
members; [0017] wherein the aryl, heteroaryl, and cycloalkyl
substituents of R.sup.3 are optionally substituted with one to
three substituents independently selected from R.sup.14; [0018]
wherein R.sup.14 is independently hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.2-6alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; and any one of
the foregoing C.sub.1-6alkyl- or C.sub.1-6alkoxy-containing
substituents of R.sup.14 is optionally substituted on a terminal
carbon atom with a substituent selected from --NR.sup.29R.sup.30,
aryl, heteroaryl, one to three halogen atoms, or hydroxy; wherein
R.sup.29 and R.sup.30 are independently hydrogen; C.sub.1-6 alkyl
optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; or aryl; and R.sup.29 and R.sup.30 are
optionally taken together with the atoms to which they are attached
to form a ring of five to seven members; [0019] n is 0 or 1; [0020]
W is O or S; [0021] X is hydrogen or C.sub.1-3alkyl; [0022] Y is
independently selected from the group consisting of C.sub.1-6alkyl
substituted with --OSO.sub.2NH.sub.2 or hydroxy; SO.sub.3H,
CO.sub.2H, heteroaryl, --OC(.dbd.O)NH.sub.2, and
P(.dbd.O)OR.sup.5R.sup.6 provided that when Y is CO.sub.2H, A and Z
must both be bicyclic ring systems; [0023] R.sup.5 is selected from
the group consisting of hydrogen; C.sub.1-6alkyl optionally
substituted with NH.sub.2, --NH(C.sub.1-6)alkyl,
--N(C.sub.1-6)dialkyl, 1,3-dioxolan-2-yl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxycarbonyloxy,
C.sub.1-6alkylcarbonylthio, (C.sub.1-6)alkylaminocarbonyl,
di(C.sub.1-6)alkylaminocarbonyl, one to three halogens, or hydroxy;
and aryl optionally substituted with C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.2-6 alkenyl, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively,
when R.sup.6 is C.sub.1-8alkoxy, R.sup.5 and R.sup.6 are taken
together with the atoms to which they are attached to form a 5-8
membered monocyclic ring; [0024] provided that R.sup.5 is other
than C.sub.1-6alkyl substituted with
di(C.sub.1-6)alkylamino-carbonyl when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z-R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-6alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3, and Z-R.sup.4 is 5-chloro-benzothiophen-3-yl; [0025]
R.sup.6 is selected from the group consisting of C.sub.1-8alkyl,
C.sub.1-8alkoxy, C.sub.2-8alkenyl, heteroaryl, aryl, and hydroxy;
wherein C.sub.1-8alkyl, C.sub.1-8alkoxy, and C.sub.2-8alkenyl are
optionally substituted with a substituent selected from the group
consisting of C.sub.1-6alkoxy, aryl, heterocyclyl, heteroaryl,
NH.sub.2, --NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylcarbonylthio;
C.sub.1-6alkoxycarbonyloxy, (C.sub.1-6)alkylaminocarbonyl,
di(C.sub.1-6)alkylaminocarbonyl, one to, three halogen atoms, and
hydroxy; and when R.sup.6 is C.sub.1-8alkyl, said C.sub.1-8alkyl is
optionally substituted with one to four additional halogen atoms
such that one to three halogen atoms are optionally chlorine and
one to seven of the halogen atoms are optionally fluorine; [0026]
wherein the heteroaryl and aryl substituents of R.sup.6 are
optionally substituted with a substituent independently selected
from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.2-6 alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, and nitro; [0027] Z is a
seven to fifteen membered monocyclic or polycyclic ring system
selected from the group consisting aryl, heteroaryl, benzo fused
heterocyclyl, or benzo fused cycloalkyl, optionally substituted
with R.sup.4; [0028] R.sup.4 is one to three substituents selected
from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkenyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, aryl(C.sub.1-6)alkyl,
aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo, and cyano;
wherein C.sub.1-6alkyl, C.sub.1-6alkenyl and C.sub.1-6alkoxy are
optionally substituted with --NR.sup.33R.sup.34, aryl, heteroaryl,
cycloalkyl, one to three halogen atoms, or hydroxy; and aryl and
heteroaryl are each optionally substituted with a substituent
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.2-6 alkenyl, C.sub.1-6alkylthio, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, one to three halogen atoms, hydroxy, and
nitro; [0029] wherein said R.sup.31, R.sup.32, R.sup.33, and
R.sup.34 are substituents independently selected from the group
consisting of hydrogen, C.sub.1-6 alkyl, and aryl, wherein alkyl is
optionally substituted with hydroxy, aryl,
--C(.dbd.O)C.sub.1-4alkoxy, NH.sub.2, NH(C.sub.1-6alkyl), or
--N(C.sub.1-6)dialkyl; and R.sup.31 with R.sup.32 and R.sup.33 with
R.sup.34 are optionally taken together with the atoms to which they
are attached to form a ring of five to seven members; and
pharmaceutically acceptable salts thereof.
[0030] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and
any of the compounds described above. An illustration of the
invention is a pharmaceutical composition made by mixing any of the
compounds described above and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing any of the compounds
described above and a pharmaceutically acceptable carrier.
[0031] The present invention is also directed to methods for
producing the instant compounds and pharmaceutical compositions and
medicaments thereof.
[0032] The present invention is further directed to methods for
treating or ameliorating a serine protease-mediated disorder. In
particular, the method of the present invention is directed to
treating or ameliorating a chymase mediated disorder such as, but
not limited to, allergic rhinitis, viral rhinitis, asthma, chronic
obstructive pulmonary diseases, bronchitis, pulmonary emphysema,
acute lung injury, psoriasis, arthritis, reperfusion injury,
ischemia, hypertension, hypercardia myocardial infarction, heart
failure damage associated with myocardial infarction, cardiac
hypertrophy, arteriosclerosis, saroidosis, vascular stenosis or
restenosis (e.g., associated with vascular injury, angioplasty,
vascular stents or vascular grafts), pulmonary fibrosis, kidney
fibrosis (e.g., associated with glomerulonephritis), liver
fibrosis, post surgical adhesion formation, systemic sclerosis,
keloid scars, rheumatoid arthritis, bullous pemphigiod, and
atherosclerosis. Additionally, these compounds can be used for
modulating wound healing and remodeling (e.g., cardiac hypertrophy)
as well as immune modulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 shows the percent change in specific lung resistance
(SR.sub.L) from baseline for Compound 17 when administered via
aerosol inhalation compared to control in a spontaneous Ascaris
suum antigen-induced model of asthma in sheep over an 8 hour
period.
[0034] FIG. 2 shows the change in the cumulative carbachol dose
required to increase SR.sub.L 400% (PC 400) from a baseline value
(BSL) measured at 24 hours post-dosing of Compound 17 via aerosol
inhalation delivery in the spontaneous Ascaris suum antigen-induced
model of asthma in sheep compared to a 24 hour post-dosing
challenge with carbachol (Post Antigen).
[0035] FIG. 3 shows the percent change in specific lung resistance
(SR.sub.L) from baseline for Compound 17 when administered via oral
administration compared to control in a spontaneous Ascaris suum
antigen-induced model of asthma in sheep over an 8 hour period.
[0036] FIG. 4 shows the change in the cumulative carbachol dose
required to increase SR.sub.L 400% (PC 400) from a baseline value
(BSL) measured at 24 hours post-dosing of Compound 17 via oral
administration in the spontaneous Ascaris suum antigen-induced
model of asthma in sheep compared to a 24 hour post-dosing
challenge with carbachol (Post Antigen).
DETAILED DESCRIPTION OF THE INVENTION
[0037] Preferred embodiments of the present invention include
compounds of Formula (I) wherein:
##STR00005##
R.sup.1 is selected from the group consisting of hydrogen and
C.sub.1-4alkyl.
[0038] More preferably, R.sup.1 is hydrogen.
[0039] Preferred embodiments of the present invention include
compounds of Formula (I) wherein:
##STR00006##
is selected from the group consisting of aryl, heteroaryl, benzo
fused heterocyclyl and benzo fused cycloalkyl optionally
substituted with R.sup.2 and R.sup.3.
[0040] Preferably, ring system A is selected from the group
consisting of heteroaryl, benzo fused heterocyclyl, or aryl.
[0041] Preferably when A is a bicyclic ring system of the
formula:
##STR00007##
wherein the a.sup.1 portion of said a.sup.1a.sup.2 is optionally
substituted with R.sup.2; and the a.sup.2 portion is optionally
substituted with R.sup.3.
[0042] Preferably a.sup.2 is an aromatic ring.
[0043] Preferably, ring system A is selected from the group
consisting of naphthyl, benzothiazolyl, benzothiophenyl,
quinolinyl, isoquinolinyl, dihydronaphthyl, indanyl, tetralinyl,
and benzodioxolyl when n is equal to zero; and A is phenyl,
pyridin-2-yl, or pyridin-3-yl when n is equal to one. In
embodiments of the present invention wherein a bicyclic ring system
is used for A, the a.sup.2 ring will be aromatic. More preferably,
ring system A is selected from the group consisting of naphthyl,
benzothiazolyl, and benzothiophenyl, when n is equal to zero, and A
is selected from phenyl, pyridin-2-yl, and, pyridin-3-yl when n is
equal to one.
[0044] A preferred embodiment of the present invention includes
compounds of Formula (I) wherein n is, equal to one.
[0045] Preferred embodiments of the present invention include
compounds of Formula (I) wherein R.sup.2 is one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, methoxy, C.sub.2-6alkoxy, --NH.sub.2,
NH(C.sub.1-6alkyl), --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
halogen, hydroxy, and nitro; wherein C.sub.1-6alkyl and
C.sub.2-6alkoxy are optionally substituted with a substituent
selected from --NR.sup.11R.sup.12, aryl, heteroaryl, one to three
halogens, and hydroxy.
[0046] More preferably, R.sup.2 is a substituent independently
selected from the group consisting of C.sub.1-4alkyl, methoxy,
C.sub.2-4alkoxy, hydroxy, halogen, and --NH.sub.2.
[0047] Most preferably, R.sup.2 is C.sub.1-4alkyl, halogen, or
--NH.sub.2.
[0048] Preferred embodiments of the present invention include
compounds of Formula (I) wherein R.sup.3 is one to three
substituents independently selected from the group consisting of
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.1-6alkoxy,
--OCH.sub.2(C.sub.2-6)alkenyl, NH.sub.2, --NH(C.sub.1-6alkyl),
--N(C.sub.1-6)dialkyl, --NHC(.dbd.O)Cy,
--N(C.sub.1-6alkyl)C(.dbd.O)Cy, --C(.dbd.O)C.sub.1-4alkoxy,
--C(.dbd.O)NR.sup.17R.sup.18, --C(.dbd.O)NHcycloalkyl,
--C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl, --C(.dbd.O)NHCy,
--C(.dbd.O)N(C.sub.1-6alkyl)Cy, --C(.dbd.O)Cy,
--OC(.dbd.O)NR.sup.19R.sup.20, halogen, hydroxy, nitro, cyano,
aryl, and aryloxy; wherein alkyl and alkoxy are optionally
substituted with one to three substituents independently selected
from the group consisting of --NR.sup.21R.sup.22, --NHcycloalkyl,
--N(C.sub.1-6alkyl)cycloalkyl --NHCy, --N(C.sub.1-6alkyl)Cy, aryl,
heteroaryl, halogen, --C(.dbd.O)NR.sup.23R.sup.24,
--OC(.dbd.O)NR.sup.25R.sup.26, --C(.dbd.O)(C.sub.1-4)alkoxy, and
--C(.dbd.O)Cy; wherein alkenyl is optionally substituted on a
terminal carbon with aryl and --C(.dbd.O)NR.sup.27R.sup.28; and
wherein aryl and cycloalkyl are optionally substituted with one to
three substituents independently selected from R.sup.14.
[0049] More preferably, R.sup.3 is one to three substituents
independently selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, --NR.sup.19R.sup.20, --NHC(.dbd.O)Cy,
--C(.dbd.O)NR.sup.17R.sup.18, --C(.dbd.O)NHcycloalkyl,
--C(.dbd.O)N(C.sub.1-6alkyl)cycloalkyl, halogen, and aryl; wherein
alkyl and alkoxy are optionally substituted on a terminal carbon
atom with one to three fluorine atoms, --NH.sub.2, --NHCy, or
--N(C.sub.1-4alkyl)Cy; and wherein aryl and cycloalkyl are
optionally substituted with a group independently selected from
R.sup.14.
[0050] Even more preferably, R.sup.3 is one to two substituents
independently selected from trifluoromethyl, C.sub.1-4alkoxy
optionally substituted with one to three fluorine atoms,
--NH.sub.2, --NHC(.dbd.O)Cy, or halogen.
[0051] Preferably when R.sup.3 is NHC(.dbd.O)Cy then Cy is
preferably piperadinyl, and substituted with a substituent selected
from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkylC(.dbd.O)C.sub.1-4alkyl,
--C.sub.1-4alkylC(.dbd.O)C.sub.1-4alkoxy,
C.sub.1-4alkylC(.dbd.O)aryl, --C(.dbd.O)(C.sub.1-4)alkyl,
--C(.dbd.O)(C.sub.1-4)alkoxy, --C(.dbd.O)aryl, --SO.sub.2aryl,
aryl, heteroaryl, and heterocyclyl; wherein aryl and the aryl
portion of the C.sub.1-4alkylC(.dbd.O)aryl, --C(.dbd.O)aryl, and
--SO.sub.2aryl is optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, hydroxy, NH.sub.2,
NH(C.sub.1-6alkyl), and --N(C.sub.1-4)dialkyl; and wherein
heterocyclyl is optionally substituted with aryl, one to three
halogen atoms, or one oxo substituents.
[0052] Most preferably, R.sup.3 is trifluoromethyl, one to two
fluorine atoms, chloro, methoxy, trifluoromethoxy, or NH.sub.2;
furthermore, when A is naphthyl and n is equal to zero, R.sup.3 is
(4-{[1-(naphthalene-2-carbonyl)-piperadine-4-carbonyl]-amino}-naphthalene-
-2-yl.
[0053] Preferred embodiments of the present invention include
compounds of Formula (I) wherein X is hydrogen or
C.sub.1-3alkyl.
[0054] More preferably, X is hydrogen.
[0055] Preferred embodiments of the present invention include
compounds of Formula (I) wherein Y is independently selected from a
group consisting of C.sub.1-3alkyl, SO.sub.3H, CO.sub.2H,
heteroaryl, --OC(.dbd.O)NH.sub.2, and P(.dbd.O)OR.sup.5R.sup.6;
wherein alkyl is substituted with a substituent selected from the
group consisting of --OSO.sub.2NH.sub.2 and hydroxy.
[0056] More preferably, Y is independently SO.sub.3H or
P(.dbd.O)OR.sup.5R.sup.6.
[0057] Most preferably, Y is P(.dbd.O)OR.sup.5R.sup.6.
[0058] Preferred embodiments of the present invention include
compounds of Formula (I) wherein R.sup.5 is selected from the group
consisting of hydrogen; C.sub.1-3alkyl optionally substituted with
NH.sub.2, --NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxy-carbonyloxy,
C.sub.1-6alkylcarbonylthio, (C.sub.1-6)alkylaminocarbonyl,
di(C.sub.1-6)alkylamino-carbonyl, one to three halogens, or
hydroxy; and aryl optionally substituted with C.sub.1-6alkyl,
C.sub.1-6alkoxy, C.sub.1-6alkylthio, C.sub.2-6 alkenyl, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, or nitro; alternatively,
when R.sup.6 is C.sub.1-8alkoxy, R.sup.5 and R.sup.6 are taken
together with the atoms to which they are attached to form a 5-8
membered monocyclic ring;
provided that R.sup.5 is other than C.sub.1-6alkyl substituted with
di(C.sub.1-6)alkylaminocarbonyl when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z-R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-6alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3, and Z-R.sup.4 is 5-chloro-benzothiophen-3-yl.
[0059] More preferably, R.sup.5 is selected from the group
consisting of hydrogen, C.sub.1-3alkyl optionally substituted with
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxycarbonyloxy,
C.sub.1-6alkyl-carbonylthio, (C.sub.1-6)alkylaminocarbonyl,
di(C.sub.1-6)alkylaminocarbonyl, one to three halogens, or
hydroxyl; and aryl; alternatively, when R.sup.6 is C.sub.1-8alkoxy,
R.sup.5 and R.sup.6 are taken together with the atoms to which they
are attached to form a 6-7 membered monocyclic ring;
provided that R.sup.5 is other than C.sub.1-3alkyl substituted with
di(C.sub.1-6)alkylaminocarbonyl when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z-R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3; and Z-R.sup.4 is 5-chloro-benzothiophen-3-yl.
[0060] Most preferably, R.sup.5 is hydrogen or C.sub.1-3alkyl
optionally substituted with C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkoxycarbonyloxy, C.sub.1-6alkylcarbonylthio,
(C.sub.1-6)alkylamino-carbonyl, or di(C.sub.1-6)alkylaminocarbonyl;
and alternatively, when R.sup.6 is C.sub.1-8alkoxy, R.sup.5 and
R.sup.6 are taken together with the atoms to which they are
attached to form a 6-membered monocyclic ring; provided that
R.sup.5 is other than C.sub.1-3alkyl substituted with
di(C.sub.1-6)alkylaminocarbonyl when ring system A is
3,4-difluoro-phenyl, n is 1, R.sup.6 is OH, and Z-R.sup.4 is
5-chloro-benzothiophen-3-yl; and provided that R.sup.5 is other
than C.sub.1-3alkyl substituted with C.sub.1-6alkylcarbonylthio
when ring system A is 3,4-difluoro-phenyl, n is 1, R.sup.6 is
CH.sub.3, and Z-R.sup.4 is 5-chloro-benzothiophen-3-yl.
[0061] Preferred embodiments of the present invention include
compounds of Formula (I) wherein R.sup.6 is selected from the group
consisting of C.sub.1-8alkyl, C.sub.1-8alkoxy, C.sub.2-8alkenyl,
heteroaryl, aryl, and hydroxy; wherein alkyl, alkoxy, and alkenyl
are optionally substituted on a terminal carbon atom with a
substituent independently selected from the group consisting of
C.sub.1-4alkoxy, aryl, heteroaryl, heterocyclyl,
C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylcarbonylthio,
C.sub.1-6alkoxycarbonyloxy, (C.sub.1-6)alkylaminocarbonyl,
di(C.sub.1-6)alkyl-aminocarbonyl, and hydroxy; and wherein
heteroaryl and aryl are optionally substituted with one to three
substituents independently selected from the group consisting of
aryl, hydroxy, C.sub.1-6alkoxy, and halogen.
[0062] More preferably, R.sup.6 is selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-8alkoxy, heteroaryl, aryl,
and hydroxy; wherein alkyl and is optionally substituted on a
terminal carbon atom with a substituent selected from
C.sub.1-3alkoxy, aryl, or hydroxy; and alkoxy is optionally
substituted on a terminal carbon with a substituent independently
selected from the group consisting of C.sub.1-6alkylcarbonyloxy,
and di(C.sub.1-6)alkyl-aminocarbonyl; and wherein heteroaryl and
aryl are optionally substituted with one to three substituents
independently selected from the group consisting of aryl, hydroxy,
C.sub.1-6alkoxy, and halogen.
[0063] Most preferably, R.sup.6 is selected from the group
consisting of methyl, ethyl, methoxypropyl, phenethyl,
benzo[1,3]dioxol-5-yl-propyl, hydroxy, and C.sub.1-3alkoxy
optionally substituted with C.sub.1-6alkylcarbonyloxy, and
di(C.sub.1-6)alkylaminocarbonyl.
[0064] Preferred embodiments of the present invention include
compounds of Formula (I) wherein Z is a bicyclic aryl or bicyclic
heteroaryl; wherein aryl and heteroaryl are optionally substituted
with the group R.sup.4; provided that when Y is CO.sub.2H, A must
be a bicycle.
[0065] More preferably, Z is selected from the group consisting of
indolyl, benzothiophenyl, naphthalenyl, quinolinyl, isoquinolinyl
and benzothiazolone.
[0066] Most preferably, Z is selected from the group consisting of
indolyl, benzothiophenyl, and naphthalenyl.
[0067] Embodiments of the present invention include compounds of,
Formula (I) wherein R.sup.4 is one to three substituents selected
from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkenyl, C.sub.1-6alkoxy, aryl(C.sub.2-6)alkenyl, halogen;
--C(.dbd.O)Cy, --C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H;
OXO, and cyano; wherein alkyl and alkoxy are optionally substituted
on a terminal carbon atom with a substituent selected from aryl,
--NR.sup.33R.sup.34, one to three halogens, or hydroxy; wherein
aryl is optionally substituted with one to three substituents
independently selected from from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.2-6 alkenyl, --NH.sub.2,
--NH(C.sub.1-6)alkyl, --N(C.sub.1-6)dialkyl, aryl, heteroaryl,
aryloxy, heteroaryloxy, halogen, hydroxy, and nitro.
[0068] Preferably, R.sup.4 is one to three substituents selected
from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkenyl,
C.sub.1-6alkoxy, aryl(C.sub.2-6)alkenyl, halogen, --C(.dbd.O)Cy,
--C(.dbd.O)NR.sup.31R.sup.32, aryl, --CO.sub.2H, oxo, and cyano;
wherein alkyl and alkoxy are optionally substituted with a
substituent independently selected from --NR.sup.33R.sup.34, aryl,
one to three halogen atoms, or hydroxy; wherein aryl is optionally
substituted with a substituent independently selected from the
group consisting of hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy,
aryl, halogen, hydroxy, and nitro.
[0069] More preferably, R.sup.4 is one to three substituents
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkenyl, aryl(C.sub.2-6)alkenyl, halogen, and
--C(.dbd.O)Cy; wherein aryl is optionally substituted with a
substituent selected from halogen and C.sub.1-4alkoxy.
[0070] Most preferably, R.sup.4 is one to two substituents selected
from the group consisting of fluorine, chlorine, bromine, methyl,
phenyl(C.sub.2-6)alkenyl, and
--C(.dbd.O)(2-(4-phenyl-piperidin-1-ylcarbonyl)).
[0071] Embodiments of the phosphonic and phosphinic acids of the
present invention include those compounds of Formula (Ia) wherein
the substituents are as previously defined (including the
previously listed preferred substitutions in any combination).
Examples of embodiments of the present invention are shown in Table
I:
TABLE-US-00001 TABLE I (Ia) ##STR00008## Cpd ##STR00009## R.sup.5
R.sup.6 n W Z--R.sup.4 1 naphthalen-2-yl H CH.sub.3 0 O
5-Cl-N-methyl-indol-3-yl 2 3,4-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 3 naphthalen-2-yl H OH 0 O
5-Cl-N-methyl-indol-3-yl 4 4-fluoro-phenyl H OH 1 O
5-Cl-N-methyl-indol-3-yl 5 naphthalen-2-yl H OH 0 O
5-Me-benzothiophen-2-yl 6 3-fluoro-phenyl H CH.sub.3 1 O
5-Cl-N-methyl-indol-3-yl 7 3,4-difluoro-phenyl H CH.sub.3 1 O
5-Cl-N-methyl-indol-3-yl 8 4-{[1-(naphthalen-2- H OH 0 O
naphthalen-1-yl ylcarbonyl)-piperadin-4- ylcarbonyl]-
amino}naphthalen-2-yl 9 naphthalen-2-yl H OH 0 O
5-Cl-benzothiophen-3-yl 10 naphthalen-2-yl H OH 0 O
5-F-benzothiophen-3-yl 11 naphthalen-2-yl H OH 0 O
5-F-N-methyl-indol-3-yl 12 4-amino-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 13 naphthalen-2-yl H OH 0 O
5-Br-N-methyl-indol-3-yl 14 Phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 15 3-fluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 16 3,4-trifluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 17 3,4-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 18 phenyl H OH 1 O 5-Cl-benzothiophen-2-yl
19 4-fluoro-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl 20
naphthalen-2-yl H CH.sub.3 0 O 5-Cl-benzothiophen-3-yl 21
2-fluoro-phenyl H CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 22
naphthalen-2-yl H OH 0 O N-methyl-indol-3-yl 23 naphthalen-2-yl H
OH 0 O 5-Br-benzothiophen-3-yl 24 4-fluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 25 pyridin-3-yl H OH 1 O
5-Cl-benzothiophen-3-yl 26 naphthalen-2-yl H OH 0 O
benzothiophen-3-yl 27 naphthalen-2-yl H OH 0 O
N-(3-phenyl-allyl)-indol-yl 28 naphthalen-2-yl H CH.sub.2CH.sub.3 0
O 5-Cl-benzothiophen-3-yl 29 3,4-difluoro-phenyl H CH.sub.2CH.sub.3
1 O 5-Cl-benzothiophen-3-yl 30 benzothiazol-6-yl H OH 0 O
5-Cl-benzothiophen-3-yl 31 naphthalen-2-yl H OH 0 O naphthalen-1-yl
32 naphthalen-2-yl H CH.sub.3 0 O 2-(4-phenyl-piperidin-1-
ylcarbonyl)-benzothiophen-3-yl 33 naphthalen-2-yl H CH.sub.3 0 O
naphthalen-1-yl 34 naphthalen-2-yl H 3-methoxy- 0 O
5-Cl-benzothiophen-3-yl propyl 35 naphthalen-2-yl H CH.sub.3 0 O
2-(4-(4-methoxyphenyl)- piperidin-1-ylcarbonyl)- benzothiophen-3-yl
36 naphthalen-2-yl H phenethyl 0 O 5-Cl-benzothiophen-3-yl 37
phenyl H OH 1 O naphthalen-1-yl 38 4-methoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 39 naphthalen-2-yl H 3-(benzo[1, 0 O
5-Cl-benzothiophen-3-yl 3]dioxol- 5-yl)-propyl 40 naphthalen-2-yl H
3-(naphthylen- 0 O 5-Cl-benzothiophen-3-yl 1yl) propyl 41
naphthalen-2-yl H CH.sub.3 0 O 2-(4-Benzyloxycarbonyl)-
piperazin-1-ylcarbonyl))- benzothiophen-3-yl 42 4-methyl-phenyl H
OH 1 O 5-Cl-benzothiophen-2-yl 43 naphthalen-2-yl H 3-(4- 0 O
5-Cl-benzothiophen-3-yl hydroxyphenyl) propyl 44
3-((N-benzoyl-piperidin- H OH 0 O naphthalen-1-yl
4-ylamino)-methyl)- naphthalen-2-yl 45 naphthalen-2-yl H OH 0 S
5-Cl-benzothiophen-3-yl 46 3-[(1-phenyl)-cyclohex- H OH 0 O
naphthalen-1-yl 1-enyl-N-methyl- aminocarbonyl]- naphthalen-2-yl 47
naphthalen-2-yl H CH.sub.3 0 O 2-((4-F-phenyl)-piperidin-
1-ylcarbonyl)- benzothiophen-3-yl 48 naphthalen-2-yl H (3-phenyl) 0
O 5-Cl-benzothiophen-3-yl propyl 49 3,4-dimethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 51 naphthalen-2-yl H (4-phenyl) 0 O
5-Cl-benzothiophen-3-yl butyl 52 naphthalen-2-yl H OH 0 O
6-Cl-N-methyl-indol-3-yl 53 naphthalen-2-yl H 3-(4-methoxy- 0 O
5-Cl-benzothiophen-3-yl phenyl) propyl 54 3-[4-((3-phenethyl)- H OH
0 O naphthalen-1-yl pyrrolidin-1- ylcarbonyl)]- naphthalen-2-yl 55
benzothiophen-5-yl H OH 0 O 5-Cl-benzothiophen-3-yl 56
naphthalen-2-yl H OH 0 O 5-carboxy-N-Me-indol-3-yl 57 quinolin-3-yl
H OH 0 O naphthalen-1-yl 58 naphthalen-2-yl H OH 0 O
7-Cl-N-methyl-indol- 3-yl 59 benzo[b]thiophen-6-yl H OH 0 O
naphthalen-1-yl 60 3-[4-(6-chloro-2-oxo- H OH 0 O naphthalen-1-yl
2,3-dihydro- benzoimidazol-1-yl)- piperidin-1-ylcarbonyl]-
naphthalen-2-yl 61 4-biphenyl H OH 0 O naphthalen-1-yl 62
naphthalen-2-yl H OH 0 O N-cyclopropyl methyl-indol-3-yl 63
naphthalen-2-yl H OH 0 O 4-Cl-N-methyl-indol-3-yl 64
benzothiophen-2-yl H OH 0 O naphthalen-1-yl 65 naphthalen-2-yl H OH
0 O 5-cyano-N-methyl-indol-3-yl 66 4-hydroxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 67 (6-Br)-naphthalen-2-yl H OH 0 O
5-Cl-benzothiophen-3-yl 68 naphthalen-2-yl H OH 0 O Indol-3-yl 69
2-amino- H OH 0 O 5-Cl-benzothiophen-3-yl benzothiazol-6-yl 70
3-(Cyclohexylamino) H OH 0 O naphthalen-1-yl methyl-naphthalen-2-yl
71 naphthalen-2-yl H OH 0 O 5-Ph-benzothiophen-3-yl 72
3-(N-benzyl-amino- H OH 0 O naphthalen-1-yl carbonyloxymethyl)
naphthalen-2-yl 73 3-(pyridin-4-yl- H OH 0 O naphthalen-1-yl
pyrrolidin-1-ylcarbonyl)- naphthalen-2-yl 74 naphthalen-2-yl H OH 0
O 5-methoxy-N-methyl- indol-3-yl 75 3-(methoxycarbonyl)- H OH 0 O
naphthalen-1-yl naphthalen-2-yl 76 naphthalen-2-yl H OH 0 O
6-Br-benzothiophen-3-yl 77 naphthalen-2-yl H OH 0 O
N-isopropyl-indol-3-yl 78 4-chloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 79 quinolin-6-yl H OH 0 O naphthalen-1-yl
81 4-trifluoromethyl-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl 82
naphthalen-2-yl H OH 0 O N-phenyl-indol-3-yl 83 4-(1H-indol-3-yl)-
H OH 0 O naphthalen-1-yl piperidin-1-ylcarbonyl)- naphthalen-2-yl
85 indanyl H OH 0 O naphthalen-1-yl 86 naphthalen-2-yl H OH 0 O
5-Cl-1,1-dioxo- benzothiophen-3-yl 87 ((3-phenyl)pyrrolidin-1- H OH
0 O naphthalen-1-yl ylcarbonyl)-naphthalen- 2-yl 89 naphthalen-2-yl
H Ph 0 O naphthalen-1-yl 90 ((3-methyl)- H OH 0 O naphthalen-1-yl
cyclohexylamino)methyl- naphthalen-2-yl 91 3-(cyclopentyl-N- H OH 0
O naphthalen-1-yl methylamino-carbonyl)- naphthalen-2-yl 92
3-((5-methoxy- H OH 0 O naphthalen-1-yl carbonyl)aminomethyl)-
naphthalen-2-yl 93 3-(4-(2-oxo-2,3- H OH 0 O naphthalen-1-yl
dihydro-benzoimidazol- 1-yl)-piperidin-1-yl- carbonyl)-naphthalen-
2-yl 94 3-(phenylamino- H OH 0 O naphthalen-1-yl
carbonyloxy)methyl)- naphthalen-2-yl 95 3-(phenylamino- H OH 0 O
naphthalen-1-yl carbonyl)methyl- naphthalen-2-yl 96 quinolin-2-yl H
OH 0 O naphthalen-1-yl 97 3-((4-phenoxy-phenyl)- H OH 0 O
naphthalen-1-yl aminocarbonyloxy- methyl)naphthalen-2-yl 98
naphthalen-2-yl H OH 0 O 5-(4-F-phenyl)-N-methyl- indol-3-yl 99
naphthalen-2-yl H OH 0 O 4-Br-benzo thiophen-3-yl 100
3-[(4-benzotriazol-1-yl- H OH 0 O naphthalen-1-yl
piperidin-1-ylcarbonyl)]- naphthalen-2-yl 101
3-(4-phenyl)-piperidin- H OH 0 O naphthalen-1-yl 1-ylcarbonyl)-
naphthalen-2-yl 102 3-((naphthalen-2- H OH 0 O naphthalen-1-yl
ylcarbonyl)piperidin-4- ylmethylamino-methyl)- naphthalen-2-yl 103
3-((3-benzenesulfonyl)- H OH 0 O naphthalen-1-yl
pyrrolidin-1-ylcarbonyl)- naphthalen-2-yl 104 3-(N-[3-(4-oxo-1- H
OH 0 O naphthalen-1-yl phenyl-1,3,8-triaza- spiro[4.5]
decane-8-carbonyl)- naphthalen-2-yl 105 3-(naphthalen-2- H OH 0 O
naphthalen-1-yl ylaminocarbonyloxy- methyl)naphthalen-2-yl 106
2-fluoroenyl H OH 0 O naphthalen-1-yl 107 3-(benzylaminomethyl)- H
OH 0 O naphthalen-1-yl naphthalen-2-yl 108 (3-OH)naphthalen-2-yl H
OH 0 O naphthalen-1-yl 109 3-(N-benzyl-3- H OH 0 O naphthalen-1-yl
acrylamide)naphthalen- 2-yl 110 3-((5-phenyl)- H OH 0 O
naphthalen-1-yl pentylamino)- naphthalen-2-yl 111
3-(N-benzyl-N-methyl- H OH 0 O naphthalen-1-yl aminocarbonyl)-
naphthalen-2-yl 112 3-[(5H-dibenzo- H OH 0 O naphthalen-1-yl
[a,d]cyclohepten-5-yl)- propyl]-methyl-amino-
methyl-naphthalen-2-yl 113 3-(4-(benzothiazol-2-yl- H OH 0 O
naphthalen-1-yl piperidin-1-ylcarbonyl))- naphthalen-2-yl 114
1-(2-oxo-2-(4-phenyl- H OH 0 O naphthalen-1-yl
piperidin-1-yl)-ethoxy)- naphthalen-2-yl 115 3-([2-(3,4-dimethoxy-
H OH 0 O naphthalen-1-yl phenyl)-ethyl]-N- methylaminocarbonyl)-
naphthalen-2-yl 116 naphthalen-2-yl H OH 0 O 1-Me-1H-pyrrolo[2,3-
b]pyridine 117 3-((4-OH- H OH 0 O naphthalen-1-yl cyclohexylamino)-
methyl)naphthalen-2-yl 118 naphthalen-2-yl H CH.sub.3 0 O
2-carboxy- benzothiophen-3-yl 119 3-(benzyl- H OH 0 O
naphthalen-1-yl aminocarbonyl)- naphthalen-2-yl 121
3-(3-phenyl-allyloxy)- H OH 0 O naphthalen-1-yl naphthalen-2-yl 122
3-(benzyloxy)- H OH 0 O naphthalen-1-yl naphthalen-2-yl 123
3-(methoxycarbonyl- H OH 0 O naphthalen-1-yl methoxy)naphthalen-
2-yl 124 3-(cyclopentylamino- H OH 0 O naphthalen-1-yl
methyl)naphthalen-2-yl 125 naphthalen-2-yl H OH 0 O
5-Cl-benzothiophen-2-yl 126 3-(phenethyl- H OH 0 O naphthalen-1-yl
methylaminomethyl) naphthalen-2-yl 127 naphthalen-2-yl H CH.sub.3 0
O 2-(benzylaminocarbonyl)- benzothiophen-3-yl 128 naphthalen-2-yl H
OH 0 O N-phenyl-indol-4-yl 129 indol-5-yl H OH 0 O naphthalen-1-yl
130 3-(3-phenyl- H OH 0 O naphthalen-1-yl propylcarbamoyl)-
methoxy)-naphthalen- 2-yl 131 3-(2-phenyl-pyrrolidin- H OH 0 O
naphthalen-1-yl 1-ylcarbonyl)- naphthalen-2-yl 132
3-amino-naphthalen- H OH 0 O naphthalen-1-yl 2-yl
133 3-((5-hydroxy- H OH 0 O naphthalen-1-yl pentylamino)-methyl)-
naphthalen-2-yl 134 1-(methoxycarbonyl- H OH 0 O naphthalen-1-yl
methoxy)-naphthalen- 2-yl 135 benzo[1,3]dioxolyl H OH 0 O
naphthalen-1-yl 137 isoquinolin-3-yl H OH 0 O naphthalen-1-yl 138
3-phenoxy-phenyl H OH 0 O naphthalen-1-yl 139 3-(isopropyloxy- H OH
0 O naphthalen-1-yl carbonyl)-naphthalen- 2-yl 140 naphthalen-2-yl
H OH 0 O benzothiophen-2-yl 141 3-{[1-(naphthalen-2- H OH 0 O
naphthalen-1-yl ylcarbonyl)-piperidin-4- ylcarbonyl]-amino}-
naphthalen-2-yl 142 3-(benzylmethyl- H OH 0 O naphthalen-1-yl
aminomethyl)- naphthalen-2-yl 143 naphthalen-2-yl H OH 0 O
6-(4-butylphenyl)- benzothiophen-3-yl 144 trans 2- H CH.sub.3 0 O
5-Cl-benzothiophen-3-yl phenylcycloprop-1-yl 145 2-methoxy-phenyl H
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 146 benzofuran-2-yl H CH.sub.3
0 O 5-Cl-benzothiophen-3-yl 147 2-nitro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 148 2-methylcarbonyloxy- H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl 149 2-hydroxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 150 pyridin-2-yl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 151 2-amino-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 152 3-trifluoromethyl-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 153 3-trifluoromethoxy- H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl 154 3-methoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 155 2-methyl-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 156 2,6-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 157 4-cyano-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 158 2-ureido-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 159 2-(NHC(.dbd.O)).sub.2NH.sub.2- H
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl phenyl 160 2-chloro-phenyl H
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 161 3-chloro-phenyl H CH.sub.3
1 O 5-Cl-benzothiophen-3-yl 162 3,5-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 163 2,3-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 164 2-bromo-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 165 2,3-dimethoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 166 3-nitro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 167 3-bromo-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 168 3,5-dimethoxy-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 169 2,5-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 170 3,5-dichloro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 171 2,4-difluoro-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 172 3-amino-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 173 phenyl --CH.sub.2C(Me).sub.2CH.sub.2O--
1 O naphthalen-1-yl 174 phenyl 3-methoxy- OH 1 O naphthalen-1-yl
prop-1-yl 175 phenyl 3-methoxy- 3-methoxy- 1 O naphthalen-1-yl
prop-1-yl prop-1-yl-oxy 176 phenyl 2-(1,3- OH 1 O naphthalen-1-yl
dioxolan-2- yl)-eth-1-yl 177 phenyl --CH.sub.2OC(.dbd.O) OH 1 O
naphthalen-1-yl t-butyl 178 phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1
O naphthalen-1-yl 179 phenyl (2-dimethyl- 2-dimethyl- 1 O
naphthalen-1-yl amino)- amino- eth-1-yl ethoxy 180 phenyl
--CH.sub.2C(.dbd.O) --OCH.sub.2C(.dbd.O) 1 O naphthalen-1-yl
NEt.sub.2 NEt.sub.2 181 phenyl --(CH.sub.2).sub.2S
--O(CH.sub.2).sub.2S 1 O naphthalen-1-yl C(.dbd.O) t-butyl
C(.dbd.O) t-butyl 182 3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O)
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl 183
3,4-difluoro-phenyl (2-dimethyl- CH.sub.3 1 O
5-Cl-benzothiophen-3-yl amino)- eth-1-yl 184 3,4-difluoro-phenyl
(2-amino)- CH.sub.3 1 O 5-Cl-benzothiophen-3-yl eth-1-yl 185
3,4-difluoro-phenyl --CH.sub.3C(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl NEt.sub.2 186 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 187 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 188
3,4-difluoro-phenyl --CH.sub.2C(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl NEt.sub.2 C(.dbd.O) NEt.sub.2 189
3,4-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 190 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl methyl 191
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 192 2-methoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 193 pyridin-2-yl H OH 1 O
5-Cl-benzothiophen-3-yl 194 3-trifluoromethoxy- H OH 1 O
5-Cl-benzothiophen-3-yl phenyl 195 3-methoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 196 2,6-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 197 2-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 198 3-chloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 199 3,5-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 200 2,3-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 201 2-bromo-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 202 2,3-dimethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 203 3-nitro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 204 3-bromo-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 205 3,5-dimethoxy-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 206 2,5-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 207 3,5-dichloro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 208 2,4-difluoro-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 209 3-amino-phenyl H OH 1 O
5-Cl-benzothiophen-3-yl 210 2-methoxy-phenyl --CH.sub.2OC(.dbd.O)
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl 211 pyridin-2-yl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
212 3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl t-butyl 213 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
214 2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 215 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
216 3-chloro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 217 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
218 2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 219 2-bromo-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
220 2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 221 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
222 3-bromo-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 223 3,5-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
224 2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 225 3,5-dichloro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
226 2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 227 3-amino-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
228 2-methoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 229 pyridin-2-yl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 230 3-trifluoromethoxy-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl OC(.dbd.O) t-butyl 231 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 232 2,6-difluoro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 233 2-chloro-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
234 3-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 235
3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 236
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 237
2-bromo-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 238
2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 239
3-nitro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 240
3-bromo-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 241
3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 242
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 243
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 244
2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 245
3-amino-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 246
2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 247 pyridin-2-yl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 248 3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl phenyl t-butyl 249 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 250
2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 251 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 252
3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 253 3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 254 2,3-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 255
2-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 256 2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 257 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 258
3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 259 3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 260 2,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 261
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 262 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 263
3-amino-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 264 2-methoxy-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 265 pyridin-2-yl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 266
3-trifluoromethoxy- --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl phenyl 267 3-methoxy-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 268
2,6-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 269 2-chloro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 270
3-chloro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 271 3,5-difluoro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 272
2,3-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 273 2-bromo-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 274
2,3-dimethoxy-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 275 3-nitro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 276
3-bromo-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 277 3,5-dimethoxy-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 278
2,5-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 279 3,5-dichloro-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 280
2,4-difluoro-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 281 3-amino-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 282
2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 283 pyridin-2-yl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
284 3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl phenyl isopropyloxy 285 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
286 2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 287 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
288 3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 289 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
290 2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 291 2-bromo-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
292 2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 293 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
294 3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 295 3,5-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
296 2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 297 3,5-dichloro-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
298 2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 299 3-amino-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
300 3-fluoro-5-chloro- H CH.sub.3 1 O 5-Cl-benzothiophen-3-yl
phenyl 301 2-fluoro-3-chloro- H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl 302 4-fluoro-3-chloro- H CH.sub.3 1
O 5-Cl-benzothiophen-3-yl phenyl 303 2-fluoro-5-chloro- H CH.sub.3
1 O 5-Cl-benzothiophen-3-yl phenyl 304 3,5-dibromo-phenyl H
CH.sub.3 1 O 5-Cl-benzothiophen-3-yl 305 3-cyano-phenyl H CH.sub.3
1 O 5-Cl-benzothiophen-3-yl 306 2-cyano-phenyl H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl 307 3-fluoro-5- H CH.sub.3 1 O
5-Cl-benzothiophen-3-yl trifluoromethyl-phenyl 308
3-fluoro-5-chloro- H OH 1 O 5-Cl-benzothiophen-3-yl phenyl 309
2-fluoro-3-chloro- H OH 1 O 5-Cl-benzothiophen-3-yl phenyl 310
4-fluoro-3-chloro- H OH 1 O 5-Cl-benzothiophen-3-yl phenyl 311
2-fluoro-5-chloro- H OH 1 O 5-Cl-benzothiophen-3-yl phenyl 312
3,5-dibromo-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl 313
3-cyano-phenyl H OH 1 O 5-Cl-benzothiophen-3-yl 314 2-cyano-phenyl
H OH 1 O 5-Cl-benzothiophen-3-yl 315 3-fluoro-5- H OH 1 O
5-Cl-benzothiophen-3-yl trifluoromethyl-phenyl 316
3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl t-butyl 317 2-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl 318 4-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl phenyl t-butyl 319 2-fluoro-5-chloro-
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl 320 3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 321 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl t-butyl
322 2-cyano-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3 1 O
5-Cl-benzothiophen-3-yl t-butyl 323 3-fluoro-5-
--CH.sub.2OC(.dbd.O) CH.sub.3 1 O 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl t-butyl 324 3-fluoro-5-chloro-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl OC(.dbd.O) t-butyl 325 2-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl OC(.dbd.O) t-butyl 326 4-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl OC(.dbd.O) t-butyl 327 2-fluoro-5-chloro-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl phenyl
t-butyl OC(.dbd.O) t-butyl 328 3,5-dibromo-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
t-butyl OC(.dbd.O) t-butyl 329 3-cyano-phenyl --CH.sub.2OC(.dbd.O)
--OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl
330 2-cyano-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 331 3-fluoro-5-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 1 O 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl t-butyl OC(.dbd.O) t-butyl 332
3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl phenyl t-butyl 333 2-fluoro-3-chloro-
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl phenyl t-butyl
334 4-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl phenyl t-butyl 335 2-fluoro-5-chloro-
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl phenyl t-butyl
336 3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl t-butyl 337 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl t-butyl 338
2-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
t-butyl 339 3-fluoro-5- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl trifluoromethyl-phenyl t-butyl 340
3-fluoro-5-chloro- --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl phenyl 341 2-fluoro-3-chloro-
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl phenyl
342 4-fluoro-3-chloro- --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl phenyl 343 2-fluoro-5-chloro-
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl phenyl
344 3,5-dibromo-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 345 3-cyano-phenyl
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl 346
2-cyano-phenyl --CH.sub.2CH.sub.2CH.sub.2O-- 1 O
5-Cl-benzothiophen-3-yl 347 3-fluoro-5-
--CH.sub.2CH.sub.2CH.sub.2O-- 1 O 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl 348 3-fluoro-5-chloro- --CH.sub.2OC(.dbd.O)
OH 1 O 5-Cl-benzothiophen-3-yl phenyl isopropyloxy 349
2-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl
phenyl isopropyloxy 350 4-fluoro-3-chloro- --CH.sub.2OC(.dbd.O) OH
1 O 5-Cl-benzothiophen-3-yl phenyl isopropyloxy 351
2-fluoro-5-chloro- --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl phenyl isopropyloxy 352 3,5-dibromo-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
353 3-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 1 O
5-Cl-benzothiophen-3-yl isopropyloxy 354 2-cyano-phenyl
--CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl isopropyloxy
355 3-fluoro-5- --CH.sub.2OC(.dbd.O) OH 1 O 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl isopropyloxy
[0072] Embodiments of the present invention include those compounds
of Formula (II) shown in Table II:
TABLE-US-00002 TABLE 2 (II) ##STR00010## Cpd Y 50 --SO.sub.3H 80
--OC(.dbd.O)NH.sub.2 84 --CO.sub.2H 88 ##STR00011## 120
--CH.sub.2OSO.sub.2NH.sub.2 136 --CH.sub.2OH
[0073] Preferred embodiments of the phosphonic and phosphinic acids
of the present invention include those compounds of Formula (Ib)
wherein the substituents are as previously defined (including any
combinations of the preferred embodiments). Examples of some of
these embodiments are shown in Table III:
TABLE-US-00003 TABLE III (Ib) ##STR00012## Cpd ##STR00013## R.sup.6
Z--R.sup.4 1 naphthalen-2-yl CH.sub.3 5-Cl-N-methyl-indol- 3-yl 3
naphthalen-2-yl OH 5-Cl-N-methyl-indol-3-yl 5 naphthalen-2-yl OH
5-Me-benzothiophen-2-yl 8 4-{[1-(naphthalen-2-carbonyl)- OH
naphthalen-1-yl piperidin-4-ylcarbonyl]-amino}- naphthalen-2-yl 9
naphthalen-2-yl OH 5-Cl-benzothiophen-3-yl 10 naphthalen-2-yl OH
5-F-benzothiophen-3-yl 11 naphthalen-2-yl OH
5-F-N-methyl-indol-3-yl 13 naphthalen-2-yl OH
5-Br-N-methyl-indol-3-yl 20 naphthalen-2-yl CH.sub.3
5-Cl-benzothiophen-3-yl 22 naphthalen-2-yl H N-methyl-indol-3-yl 23
naphthalen-2-yl H 5-Br-benzothiophen-3-yl 26 naphthalen-2-yl OH
benzothiophen-3-yl 27 naphthalen-2-yl OH
N-(3-phenyl-allyl)-indol-3-yl 28 naphthalen-2-yl CH.sub.2CH.sub.3
5-Cl-benzothiophen-3-yl 30 benzothiazol-6-yl OH
5-Cl-benzothiophen-3-yl 31 naphthalen-2-yl OH naphthalen-1-yl 32
naphthalen-2-yl CH.sub.3 2-(4-phenyl-piperidine-1- carbonyl)-
benzothiophen-3-yl 33 naphthalen-2-yl CH.sub.3 naphthalen-1-yl 34
naphthalen-2-yl 3-methoxy- 5-Cl-benzothiophen-3-yl propyl 35
naphthalen-2-yl CH.sub.3 2-(4-(4-methoxyphenyl)-
piperidin-1-ylcarbonyl)- benzothiophen-3-yl 36 naphthalen-2-yl
phenethyl 5-Cl-benzothiophen-3-yl 39 naphthalen-2-yl 3-(benzo[1,
5-Cl-benzothiophen-3-yl 3]dioxol- 5-yl)-propyl 40 naphthalen-2-yl
3-(naphthylen- 5-Cl-benzothiophen-3-yl 1yl)propyl 41
naphthalen-2-yl CH.sub.3 2-(4-Benzyloxycarbonyl)-
piperazin-1-ylcarbonyl)- benzothiophen-3-yl 43 naphthalen-2-yl
3-(4-hydroxy- 5-Cl-benzothiophen-3-yl phenyl) propyl 44
3-((benzoyl-piperidin-4-yl- OH naphthalen-1-yl
amino)-methyl)-naphthalen-2-yl 45 naphthalen-2-yl OH
5-Cl-benzothiophen-3-yl 46 3-[(1-phenyl)-cyclohex-1-enyl- OH
naphthalen-1-yl 4-N-methylamino-carbonyl)]- naphthalen-2-yl 47
naphthalen-2-yl CH.sub.3 2-((4-F-phenyl)-piperidin-1- ylcarbonyl)-
benzothiophen-3-yl 48 naphthalen-2-yl (3-phenyl)
5-Cl-benzothiophen-3-yl propyl 51 naphthalen-2-yl (4-phenyl)
5-Cl-benzothiophen-3-yl butyl 52 naphthalen-2-yl OH
6-Cl-N-methyl-indol-3-yl 53 naphthalen-2-yl 3-(4-methoxy-
5-Cl-benzothiophen-3-yl phenyl) propyl 54
3-[4-((3-phenethyl)-pyrrolidin-1- OH naphthalen-1-yl
ylcarbonyl)]-naphthalen-2-yl 55 benzothiophen-5-yl OH
5-Cl-benzothiophen-3-yl 56 naphthalen-2-yl OH
5-carboxy-N-Me-indol-3-yl- 57 quinolin-3-yl OH naphthalen-1-yl 58
naphthalen-2-yl OH 7-Cl-N-methyl-indol-3-yl 59
benzo[b]thiophen-6-yl OH naphthalen-1-yl 60
3-[4-(6-Chloro-2-oxo-2,3- OH naphthalen-1-yl
dihydro-benzoimidazol-1-yl)- piperidin-1-ylcarbonyl]-
naphthalen-2-yl 61 p-biphenyl OH naphthalen-1-yl 62 naphthalen-2-yl
OH N-cyclopropylmethyl- indol-3-yl 63 naphthalen-2-yl OH
4-Cl-N-methyl-indol-3-yl 64 benzothiophen-2-yl OH naphthalen-1-yl
65 naphthalen-2-yl OH 5-cyano-N-methyl-indol-3-yl 67
(6-Br)-naphthalen-2-yl OH 5-Cl-benzothiophen-3-yl 68
naphthalen-2-yl OH Indol-3-yl 69 2-amino-benzothiazol-6-yl OH
5-Cl-benzothiophen-3-yl 70 3-(cyclohexylamino)methyl- OH
naphthalen-1-yl naphthalen-2-yl 71 naphthalen-2-yl OH
5-Ph-benzothiophen-3-yl 72 3-(N-benzyl-amino- OH naphthalen-1-yl
carbonyloxymethyl) naphthalen-2-yl 73 3-(pyridin-4-yl-pyrrolidin-1-
OH naphthalen-1-yl ylcarbonyl)-naphthalen-2-yl 74 naphthalen-2-yl
OH 5-methoxy-N-methyl- indol-3-yl 75 3-(methoxycarbonyl)- OH
naphthalen-1-yl naphthalen-2-yl 76 naphthalen-2-yl OH
6-Br-benzothiophen-3-yl 77 naphthalen-2-yl OH
N-isopropyl-indol-3-yl 79 quinolin-6-yl OH naphthalen-1-yl 82
naphthalen-2-yl OH N-phenyl-indol-3-yl 83
(4-(1H-indol-3-yl)-piperidin-1- OH naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl 85 Indanyl OH naphthalen-1-yl 86
naphthalen-2-yl OH 5-Cl-1,1-dioxo-benzothiophen- 3-yl 87
((3-phenyl)pyrrolidin-1- OH naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl 89 naphthalen-2-yl Ph
5-Cl-benzothiophen-3-yl 90 ((3-methyl)-cyclohexyl- OH
naphthalen-1-yl amino)methyl-naphthalen-2-yl 91
3-(cyclopentyl-N-methylamino- OH naphthalen-1-yl
carbonyl)-naphthalen-2-yl 92 3-((Hexanoic acid methyl OH
naphthalen-1-yl ester)aminomethyl)-naphthalen- 2-yl 93
3-(4-(2-oxo-2,3-dihydro- OH naphthalen-1-yl
benzoimidazol-1-yl)-piperidin-1- ylcarbonyl)-naphthalen-2-yl 94
3-(phenyl-aminocarbonyloxy)- OH naphthalen-1-yl
methyl)-naphthalen-2-yl 95 3-(phenyl-aminocarbonyl)- OH
naphthalen-1-yl methyl-naphthalen-2-yl 96 quinolin-2-yl OH
naphthalen-1-yl 97 3-((4-phenoxy-phenyl)- OH naphthalen-1-yl
aminocarbonyloxymethyl)- OH naphthalen-1-yl naphthalen-2-yl 98
naphthalen-2-yl OH 5-(4-F-phenyl)-N-methyl-indol- 3-yl 99
naphthalen-2-yl OH 4-Br-benzothiophen-3-yl 100
3-[(4-benzotriazol-1-yl-piperidin- OH naphthalen-1-yl
1-ylcarbonyl)]-naphthalen-2-yl 101 3-(4-phenyl)-piperidin-1- OH
naphthalen-1-yl ylcarbonyl)-naphthalen-2-yl 102
3-((naphthalene-2-carbonyl)- OH naphthalen-1-yl
piperidin-4-ylmethylamino- methyl)-naphthalen-2-yl 103
3-((3-benzenesulfonyl)- OH naphthalen-1-yl
pyrrolidin-1-ylcarbonyl)- naphthalen-2-yl 104
3-(N-[3-(4-oxo-1-phenyl-1,3,8- OH naphthalen-1-yl
triaza-spiro[4.5]decane-8- carbonyl)-naphthalen-2-yl 105
3-(naphthalen-2- OH naphthalen-1-yl ylaminocarbonyloxy-methyl)-
naphthalen-2-yl 106 2-fluorenyl OH naphthalen-1-yl 107
3-(benzylaminomethyl)- OH naphthalen-1-yl naphthalen-2-yl 108
(3-OH)naphthalen-2-yl OH naphthalen-1-yl 109 3-(N-benzyl-3- OH
naphthalen-1-yl acrylamide)naphthalen-2-yl 110
3-((5-phenyl)pentylamino)- OH naphthalen-1-yl naphthalen-2-yl 111
3-(N-benzyl-N-methyl-amino- OH naphthalen-1-yl
carbonyl)-naphthalen-2-yl 112 3-[(5H-dibenzo[a,d]cyclohepten- OH
naphthalen-1-yl 5-yl)-propyl]-methyl-amino- methyl-naphthalen-2-yl
113 3-(4-(benzothiazol-2-yl- OH naphthalen-1-yl
piperidine-1-carbonyl))- naphthalen-2-yl 114
1-(2-oxo-2-(4-phenyl-piperidin- OH naphthalen-1-yl
1-yl)-ethoxy)-naphthalen-2-yl 115 3-[2-(3,4-dimethoxy-phenyl)- OH
naphthalen-1-yl ethyl]-N-methyl-aminocarbonyl)- naphthalen-2-yl 116
naphthalen-2-yl OH 1-Me-1H-pyrrolo[2, 3-b]pyridine 117
3-((4-OH-cyclohexylamino)- OH naphthalen-1-yl
methyl)-naphthalen-2-yl 118 naphthalen-2-yl CH.sub.3 2-carboxy-
benzothiophen-3-yl 119 3-(benzylaminocarbonyl)- OH naphthalen-1-yl
naphthalen-2-yl 121 3-(3-phenyl-allyloxy)- OH naphthalen-1-yl
naphthalen-2-yl 122 3-(benzyloxy)-naphthalen-2-yl OH
naphthalen-1-yl 123 3-(methoxycarbonyl-methoxy)- OH naphthalen-1-yl
naphthalen-2-yl 124 3-(cyclopentylamino-methyl)- OH naphthalen-1-yl
naphthalen-2-yl 125 naphthalen-2-yl OH 5-Cl-benzothiophen-2-yl 126
3-(phenethyl-methylamino- OH naphthalen-1-yl methyl)naphthalen-2-yl
127 naphthalen-2-yl CH.sub.3 2-(benzylaminocarbonyl)-
benzothiophen-3-yl 128 naphthalen-2-yl OH N-phenyl-indol-4-yl 129
indol-5-yl OH naphthalen-1-yl 130 3-(3-phenyl-propylcarbamoyl)- OH
naphthalen-1-yl methoxy)-naphthalen-2-yl 131
3-(2-phenyl-pyrrolidin-1- OH naphthalen-1-yl
ylcarbonyl)-naphthalen-2-yl 132 3-amino-naphthalen-2-yl OH
naphthalen-1-yl 133 3-((5-hydroxypentylamino)- OH naphthalen-1-yl
134 1-(1-oxy-acetic acid methyl OH naphthalen-1-yl
ester)-naphthalen-2-yl 135 benzo[1,3]dioxolyl OH naphthalen-1-yl
137 isoquinolin-3-yl OH naphthalen-1-yl 138 3-phenoxy-phenyl OH
naphthalen-1-yl 139 3-(isopropyloxycarbonyl)- OH naphthalen-1-yl
naphthalen-2-yl 140 naphthalen-2-yl OH benzothiophen-2-yl 141
3-{[1-(naphthalen-2-ylcarbonyl)- OH naphthalen-1-yl
piperidin-4-ylcarbonyl]-amino}- naphthalen-2-yl 142
3-(benzylmethyl- OH naphthalen-1-yl aminomethyl)-naphthalen-2-yl
143 naphthalen-2-yl OH 6-(4-butylphenyl)- benzothiophen-3-yl 146
benzofuran-2-yl CH.sub.3 5-Cl-benzothiophen-3-yl
[0074] Preferred embodiments of the phosphonic and phosphinic acids
of the present invention include those compounds of Formula (Ic)
shown in Table IV:
TABLE-US-00004 TABLE IV ##STR00014## Cpd ##STR00015## R.sup.5
R.sup.6 Z-R.sup.4 2 3,4-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 4 4-fluoro-phenyl H OH
5-Cl-N-methyl-indol-3-yl 6 3-fluoro-phenyl H CH.sub.3
5-Cl-N-methyl-indol-3-yl 7 3,4-difluoro-phenyl H CH.sub.3
5-Cl-N-methyl-indol-3-yl 12 4-amino-phenyl H OH
5-Cl-benzothiophen-3-yl 14 phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 15 3-fluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 16 3,4-trifluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 17 3,4-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 18 phenyl H OH 5-Cl-benzothiophen-2-yl 19
4-fluoro-phenyl H OH 5-Cl-benzothiophen-3-yl 21 2-fluoro-phenyl H
CH.sub.3 5-Cl-benzothiophen-3-yl 24 4-fluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 25 pyridin-3-yl H OH
5-Cl-benzothiophen-3-yl 29 3,4-difluoro-phenyl H CH.sub.2CH.sub.3
5-Cl-benzothiophen-3-yl 37 phenyl H OH naphthalen-1-yl 38
4-methoxy-phenyl H OH 5-Cl-benzothiophen-3-yl 42 4-methyl-phenyl H
OH 5-Cl-benzothiophen-2-yl 49 3,4-dimethoxy-phenyl H OH
5-Cl-benzothiophen-3-yl 66 4-hydroxy-phenyl H OH
5-Cl-benzothiophen-3-yl 78 4-chloro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 81 4-trifluoromethyl-phenyl H OH
5-Cl-benzothiophen-3-yl 145 2-methoxy-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 146 benzofuran-2-yl H CH.sub.3
5-Cl-benzothiophen-3-yl 147 2-nitro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 148 2-methylcarbonyloxy- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 149 2-hydroxy-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 150 pyridin-2-yI H CH.sub.3
5-Cl-benzothiophen-3-yl 151 2-amino-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 152 3-trifluoromethyl-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 153 3-trifluoromethoxy- H CH.sub.3
5-Cl-benzothiophen-3-yl phenyl 154 3-methoxy-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 155 2-methyl-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 156 2,6-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 157 4-cyano-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 158 2-ureido-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 159 2-(NHC(.dbd.O)).sub.2NH.sub.2- H
CH.sub.3 5-Cl-benzothiophen-3-yl phenyl 160 2-chloro-phenyl H
CH.sub.3 5-Cl-benzothiophen-3-yl 161 3-chloro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 162 3,5-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 163 2,3-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 164 2-bromo-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 165 2,3-dimethoxy-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 166 3-nitro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 167 3-bromo-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 168 3,5-dimethoxy-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 169 2,5-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 170 3,5-dichloro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 171 2,4-difluoro-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 172 3-amino-phenyl H CH.sub.3
5-Cl-benzothiophen-3-yl 173 phenyl --CH.sub.2C(Me).sub.2CH.sub.2O--
naphthalen-1-yl 174 phenyl 3-methoxy- OH naphthalen-1-yl prop-1-yl
175 phenyl 3-methoxy- 3-methoxy- naphthalen-1-yl prop-1-yl
prop-1-yl- oxy 176 phenyl 2-(1,3-dioxolan- OH naphthalen-1-yl
2-yl)-eth-1-yl 177 phenyl --CH.sub.2OC(.dbd.O) OH naphthalen-1-yl
t-butyl 178 phenyl --CH.sub.2 CH.sub.2 CH.sub.2 O-- naphthalen-1-yl
179 phenyl (2-dimethylamino)- 2-dimethyl naphthalen-1-yl eth-1-yl
amino- ethoxy 180 phenyl --CH.sub.2C(.dbd.O)NEt.sub.2 --OCH.sub.2
naphthalen-1-yl C(.dbd.O)NEt.sub.2 181 phenyl
--(CH.sub.2).sub.2SC(.dbd.O) --O(CH.sub.2).sub.2S naphthalen-1-yl
t-butyl C(.dbd.O) t-butyl 182 3,4-difluoro-phenyl
1-CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 183
3,4-difluoro-phenyl (2-dimethylamino)- CH.sub.3
5-Cl-benzothiophen-3-yl eth-1-yl 184 3,4-difluoro-phenyl
(2-amino)-eth-1-yl CH.sub.3 5-Cl-benzothiophen-3-yl 185
3,4-difluoro-phenyl --CH.sub.2C(.dbd.O)NEt.sub.2 CH.sub.3
5-Cl-benzothiophen-3-yl 186 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 5-Cl-benzothiophen-3-yl t-butyl
t-butyl 187 3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl) 188 3,4-difluoro-phenyl
--CH.sub.2C(.dbd.O)NEt.sub.2 --OCH.sub.2 5-Cl-benzothiophen-3-yl
C(.dbd.O)NEt.sub.2 189 3,4-difluoro-phenyl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 190 3,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl methyl 191
3,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 192 2-methoxy-phenyl H OH 5-Cl-benzothiophen-3-yl 193
pyridin-2-yl H OH 5-Cl-benzothiophen-3-yl 194 3-trifluoromethoxy- H
OH 5-Cl-benzothiophen-3-yl phenyl 195 3-methoxy-phenyl H OH
5-Cl-benzothiophen-3-yl 196 2,6-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 197 2-chloro-phenyl H OH
5-Cl-benzothiophen-3-yl 198 3-chloro-phenyl H OH
5-Cl-benzothiophen-3-yl 199 3,5-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 200 2,3-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 201 2-bromo-phenyl H OH
5-Cl-benzothiophen-3-yl 202 2,3-dimethoxy-phenyl H OH
5-Cl-benzothiophen-3-yl 203 3-nitro-phenyl H OH
5-Cl-benzothiophen-3-yl 204 3-bromo-phenyl H OH
5-Cl-benzothiophen-3-yl 205 3,5-dimethoxy-phenyl H OH
5-Cl-benzothiophen-3-yl 206 2,5-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 207 3,5-dichloro-phenyl H OH
5-Cl-benzothiophen-3-yl 208 2,4-difluoro-phenyl H OH
5-Cl-benzothiophen-3-yl 209 3-amino-phenyl H OH
5-Cl-benzothiophen-3-yl 210 2-methoxy-phenyl --CH.sub.2OC(.dbd.O)
CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 211 pyridin-2-yl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 212
3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) t- CH.sub.3
5-Cl-benzothiophen-3-yl phenyl butyl 213 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 5-Cl-benzothiophen-3-yl butyl 214
2,6-difiuoro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3
5-Cl-benzothiophen-3-yl butyl 215 2-chloro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 216
3-chloro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 217 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 218
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 219 2-bromo-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 220
2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 221 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 222
3-bromo-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 223 3,5-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 224
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 225 3,5-dichloro-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 226
2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) CH.sub.3
5-Cl-benzothiophen-3-yl t-butyl 227 3-amino-phenyl
--CH.sub.2OC(.dbd.O) CH.sub.3 5-Cl-benzothiophen-3-yl t-butyl 228
2-methoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 229 pyridin-2-yl
--CH.sub.2OC(.dbd.O) --OCH.sub.2 5-Cl-benzothiophen-3-yl t-butyl
OC(.dbd.O) t-butyl 230 3-trifluoromethoxy- --CH.sub.2OC(.dbd.O)
--OCH.sub.2 5-Cl-benzothiophen-3-yl phenyl t-butyl OC(.dbd.O)
t-butyl 231 3-methoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 232
2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 233
2-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 234
3-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 235
3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 236
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 237
2-bromo-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 238
2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 239
3-nitro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 240
3-bromo-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 241
3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 242
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 243
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 244
2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 245
3-amino-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 246
2-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 247 pyridin-2-yl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 248 3-trifluoromethoxy-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl phenyl t-butyl 249
3-methoxy-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 250 2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl
251 2-chloro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 252 3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 253 3,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 254
2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 255 2-bromo-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 256 2,3-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 257
3-nitro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 258 3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 259 3,5-dimethoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 260
2,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 261 3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 262 2,4-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 263
3-amino-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 264 2-methoxy-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 265 pyridin-2-yl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 266 3-trifluoromethoxy-
--CH.sub.2 CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl phenyl 267
3-methoxy-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 268 2,6-difluoro-phenyl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 269 2-chloro-phenyl --CH.sub.2
CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 270 3-chloro-phenyl
--CH.sub.2 CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 271
3,5-difluoro-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 272 2,3-difluoro-phenyl --CH2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 273 2-bromo-phenyl --CH.sub.2
CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 274
2,3-dimethoxy-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 275 3-nitro-phenyl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 276 3-bromo-phenyl --CH.sub.2
CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 277
3,5-dimethoxy-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 278 2,5-difluoro-phenyl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 279 3,5-dichloro-phenyl
--CH.sub.2 CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 280
2,4-difluoro-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 281 3-amino-phenyl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 282 2-methoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 283
pyridin-2-yI --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 284 3-trifluoromethoxy- --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl phenyl isopropyloxy 285 3-methoxy-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 286
2,6-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 287 2-chloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 288 3-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothioplfen-3-yl isopropyloxy 289
3,5-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 290 2,3-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropytoxy 291 2-bromo-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 292
2,3-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 293 3-nitro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 294
3-bromo-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 295 3,5-dimethoxy-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 296 2,5-difluoro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 297
3,5-dichloro-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 298 2,4-difluoro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 299 3-amino-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 300
3-fluoro-5-chloro-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 301
2-fluoro-3-chloro-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 302
4-fluoro-3-chloro-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 303
2-fluoro-5-chloro-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 304
3,5-dibromo-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 305
3-cyano-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 306
2-cyano-phenyl H CH.sub.3 5-Cl-benzothiophen-3-yl 307 3-fluoro-5- H
CH.sub.3 5-Cl-benzothiophen-3-yl trifluoromethyl-phenyl 308
3-fluoro-5-chloro-phenyl H OH 5-Cl-benzothiophen-3-yl 309
2-fiuoro-3-chloro-phenyi H OH 5-Cl-benzothiophen-3-yl 310
4-fluoro-3-chloro-phenyl H OH 5-Cl-benzothiophen-3-yl 311
2-fluoro-5-chloro-phenyl H OH 5-Cl-benzothiophen-3-yl 312
3,5-dibromo-phenyl H OH 5-Cl-benzothiophen-3-yl 313 3-cyano-phenyl
H OH 5-Cl-benzothiophen-3-yl 314 2-cyano-phenyl H OH
5-Cl-benzothiophen-3-yl 315 3-fluoro-5- H OH
5-Cl-benzothiophen-3-yl trifluoromethyl-phenyl 316
3-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3
5-Cl-benzothiophen-3-yl butyl 317 2-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 5-Cl-benzothiophen-3-yl butyl 318
4-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3
5-Cl-benzothiophen-3-yl butyl 319 2-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 5-Cl-benzothiophen-3-yl butyl 320
3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3
5-Cl-benzothiophen-3-yl butyl 321 3-cyano-phenyl
--CH.sub.2OC(.dbd.O) t- CH.sub.3 5-Cl-benzothiophen-3-yl butyl 322
2-cyano-phenyl --CH.sub.2OC(.dbd.O) t- CH.sub.3
5-Cl-benzothiophen-3-yl butyl 323 3-fluoro-5- --CH.sub.2OC(.dbd.O)
t- CH.sub.3 5-Cl-benzothiophen-3-yl trifluoromethyl-phenyl butyl
324 3-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 325
2-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 326
4-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 327
2-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 328
3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 329
3-cyano-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 330
2-cyano-phenyl --CH.sub.2OC(.dbd.O) --OCH.sub.2
5-Cl-benzothiophen-3-yl t-butyl OC(.dbd.O) t-butyl 331 3-fluoro-5-
--CH.sub.2OC(.dbd.O) --OCH.sub.2 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl t-butyl OC(.dbd.O) t-butyl 332
3-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 333 2-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 334
4-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 335 2-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 336
3,5-dibromo-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
t-butyl 337 3-cyano-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl t-butyl 338 2-cyano-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl t-butyl 339
3-fluoro-5- --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl t-butyl 340 3-fluoro-5-chloro-phenyl
--CH.sub.2 CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 341
2-fluoro-3-chloro-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 342 4-fluoro-3-chloro-phenyl --CH.sub.2
CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 343
2-fluoro-5-chloro-phenyl --CH.sub.2 CH.sub.2 CH.sub.2O--
5-Cl-benzothiophen-3-yl 344 3,5-dibromo-phenyl --CH.sub.2 CH.sub.2
CH.sub.2O-- 5-Cl-benzothiophen-3-yl 345 3-cyano-phenyl --CH.sub.2
CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 346 2-cyano-phenyl
--CH.sub.2 CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl 347
3-fluoro-5- --CH.sub.2 CH.sub.2 CH.sub.2O-- 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl 348 3-fluoro-5-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 349
2-fluoro-3-chloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 350 4-fluoro-3-chloro-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 351
2-fluoro-5-chloro-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 352 3,5-dibromo-phenyl
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl isopropyloxy 353
3-cyano-phenyl --CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
isopropyloxy 354 2-cyano-phenyl --CH.sub.2OC(.dbd.O) OH
5-Cl-benzothiophen-3-yl isopropyloxy 355 3-fluoro-5-
--CH.sub.2OC(.dbd.O) OH 5-Cl-benzothiophen-3-yl
trifluoromethyl-phenyl isopropyloxy
[0075] A preferred embodiment of the present invention includes the
representative compounds presented in Table V.
TABLE-US-00005 TABLE V Cpd 1 ##STR00016## 2 ##STR00017## 3
##STR00018## 4 ##STR00019## 5 ##STR00020## 6 ##STR00021## 7
##STR00022## 8 ##STR00023## 9 ##STR00024## 10 ##STR00025## 11
##STR00026## 12 ##STR00027## 13 ##STR00028## 14 ##STR00029## 15
##STR00030## 16 ##STR00031## 17 ##STR00032## 18 ##STR00033## 19
##STR00034## 20 ##STR00035## 21 ##STR00036## 22 ##STR00037## 23
##STR00038## 24 ##STR00039## 25 ##STR00040## 145 ##STR00041## 149
##STR00042## 150 ##STR00043## 153 ##STR00044## 154 ##STR00045## 156
##STR00046## 160 ##STR00047## 161 ##STR00048## 162 ##STR00049## 163
##STR00050## 164 ##STR00051## 165 ##STR00052## 166 ##STR00053## 167
##STR00054## 168 ##STR00055## 169 ##STR00056## 170 ##STR00057## 171
##STR00058## 172 ##STR00059## 177 ##STR00060## 182 ##STR00061## 186
##STR00062## 187 ##STR00063## 189 ##STR00064## 191 ##STR00065##
[0076] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts." FDA approved
pharmaceutically acceptable salt forms (Ref. International J.
Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977, January, 66(1), p1)
include pharmaceutically acceptable acidic/anionic or
basic/cationic salts.
[0077] Pharmaceutically acceptable acidic/anionic salts include,
and are not limited to acetate, benzenesulfonate, benzoate,
bicarbonate, bitartrate, bromide, calcium edetate, camsylate,
carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, glyceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate,
pantothenate, phosphate/diphospate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulfate, tannate, tartrate,
teoclate, tosylate, and triethiodide. Organic or inorganic acids
also include, and are not limited to, hydriodic, perchloric,
sulfuric, phosphoric, propionic, glycolic, methanesulfonic,
hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic,
p-toluenesulfonic, cyclohexanesulfamic, saccharinic, and
trifluoroacetic acid.
[0078] Pharmaceutically acceptable basic/cationic salts include,
and are not limited to aluminum,
2-amino-2-hydroxymethyl-propane-1,3-diol (also known as
tris(hydroxy-methyl)aminomethane, tris(hydroxymethyl)methylamine,
tromethamine), ammonia, benzathine, t-butylamine, calcium,
chloroprocaine, choline, cyclohexylamine, diethanolamine,
ethylenediamine, lithium, L-lysine, magnesium, meglumine, NH.sub.3,
NH.sub.4OH, N-methyl-D-glucamine, piperidine, potassium, procaine,
quinine, SEH, sodium, triethanolamine (TEA), imidazole, and
zinc.
[0079] Compounds of the present invention may be contacted with a
pharmaceutically acceptable cation selected from the group
consisting of aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol
(also known as tris(hydroxymethyl)aminomethane,
tris(hydroxymethyl)methylamine, tromethamine), ammonia, benzathine,
t-butylamine, calcium, chloroprocaine, choline, cyclohexylamine,
diethanolamine, ethylenediamine, lithium, L-lysine, magnesium,
meglumine, NH.sub.3, NH.sub.4OH, N-methyl-D-glucamine, piperidine,
potassium, procaine, quinine, SEH, sodium, triethanolamine (TEA),
imidazole, and zinc to form a salt.
[0080] Preferred cations for use with the instant compounds are
selected from the group consisting of benzathine, t-butylamine,
calcium, choline, cyclohexylamine, diethanolamine, ethylenediamine,
L-lysine, NH.sub.3, NH.sub.4OH, N-methyl-D-glucamine, piperidine,
potassium, procaine, quinine, sodium, triethanolamine, imidazole,
and tris(hydroxymethyl)methylamine (tromethamine).
[0081] More preferably, cations for use with the instant compounds
are selected from the group consisting of t-butylamine, NH.sub.4OH,
imidazole, sodium, and tris(hydroxymethyl)methylamine
(tromethamine).
[0082] Most preferably, the cations for use with the instant
compounds are tromethamine and sodium.
[0083] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds, which are readily
convertible in vivo into an active compound. Thus, in the methods
of treatment of the present invention, the term "administering"
shall encompass the treatment of the various disorders described
with the compound specifically disclosed or a prodrug compound
which would be obviously included within the scope of the invention
although not specifically disclosed. Conventional procedures for
the selection and preparation of suitable prodrug derivatives are
described, for example, in "Design of Prodrugs", ed. H. Bundgaard,
Elsevier, 1985. Phosphonic acid prodrugs (as described in De
Lombaert S., et al, Non-Peptidic Inhibitors of Neutral
Endopeptidase 24.11; Design and Pharmacology of Orally Active
Phosphonate Prodrugs, Bioorganic and Medicinal Chemistry Letters,
1995, 5(2), 151-154; and, De Lombaert S., et al, N-Phosphonomethyl
Dipeptides and Their Phosphonate Prodrugs, a New Generation Neutral
Endopeptidase (NEP, EC 3.424.11) Inhibitors, J. Med. Chem., 1994,
37, 498-511) and phosphinic acid prodrugs are intended to be
included within the scope of the present invention.
[0084] The compounds according to this invention may have at least
one chiral center and thus may exist as enantiomers. In addition,
the compounds of the present invention may also possess two or more
chiral centers and thus may also exist as diastereomers. Where the
processes for the preparation of the present compounds give rise to
a mixture of stereoisomers, these isomers may be separated by
conventional techniques such as preparative chromatography.
Accordingly, the compounds may be prepared as a racemic mixture or,
by either enantiospecific synthesis or resolution, as individual
enantiomers. The compounds may, for example, be resolved from a
racemic mixture into their component racemates by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active base, followed by fractional
crystallization and regeneration of the compounds of this
invention. The racemic mixture may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column. It is to be
understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention.
[0085] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known in the
art.
[0086] Furthermore, some of the crystalline forms for the compounds
may exist as polymorphs and as such are intended to be included in
the present invention. In addition, some of the compounds may form
solvates with water (i.e., hydrates) or common organic solvents,
and such solvates are also intended to be encompassed within the
scope of this invention.
[0087] As used herein, unless otherwise noted, "alkyl" whether used
alone or as part of a substituent group refers to straight and
branched carbon chains having 1 to 8 carbon atoms or any number
within this range. The term "alkoxy" refers to an --Oalkyl
substituent group, wherein alkyl is as defined supra. Similarly,
the terms "alkenyl" and "alkynyl" refer to straight and branched
carbon chains having 2 to 8 carbon atoms or any number within this
range, wherein an alkenyl chain has at least one double bond in the
chain and an alkynyl chain has at least one triple bond in the
chain. An alkyl and alkoxy chain may be substituted on a terminal
carbon atom or, when acting as a linking group, within the carbon
chain.
[0088] The term "cycloalkyl" refers to saturated or partially
unsaturated, monocyclic or polycyclic hydrocarbon rings of from 3
to 20 carbon atom members (preferably from 3 to 14 carbon atom
members). Further, a cycloalkyl ring may optionally be fused to one
or more cycloalkyl rings. Examples of such rings include, and are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and adamantyl.
[0089] The term "heterocyclyl" refers to a nonaromatic cyclic ring
of 5 to 10 members in which 1 to 4 members are nitrogen or a
nonaromatic cyclic ring of 5 to 10 members in which zero, one or
two members are nitrogen and up to two members is oxygen or sulfur;
wherein, optionally, the ring contains zero, one or two unsaturated
bonds. Alternatively, the heterocyclyl ring may be fused to a
benzene ring (benzo fused heterocyclyl), a 5 or 6
membered-heteroaryl ring (containing one of O, S or N and,
optionally, one additional nitrogen), a 5 to 7 membered cycloalkyl
or cycloalkenyl ring, a 5 to 7 membered heterocyclyl ring (of the
same definition as above but absent the option of a further fused
ring) or fused with the carbon of attachment of a cycloalkyl,
cycloalkenyl or heterocyclyl ring to form a spiro moiety. For
instant compounds of the invention, the carbon atom ring members
that form the heterocyclyl ring are fully saturated. Other
compounds of the invention may have a partially saturated
heterocyclyl ring. Additionally, the heterocyclyl can be bridged to
form bicyclic rings. Preferred partially saturated heterocyclyl
rings may have from one to two double bonds. Such compounds are not
considered to be fully aromatic and are not referred to as
heteroaryl compounds. Examples of heterocyclyl groups include, and
are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl
or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl,
2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, and piperazinyl.
[0090] The term "aryl" refers to an unsaturated, aromatic
monocyclic ring of 6 carbon members or to an unsaturated, aromatic
polycyclic ring of from 10 to 20 carbon members. Examples of such
aryl rings include, and are not limited to, phenyl, naphthalenyl
and anthracenyl. Preferred aryl groups for the practice of this
invention are phenyl and naphthalenyl.
[0091] The term "benzo fused cycloalkyl" refers to a bicyclic or
tricyclic ring structure wherein at least one of the ring
substituents is phenyl or naphthalenyl and at least one of the
other substituents is a cycloalkyl ring (as cycloalkyl was
previously defined). For the purpose of these definitions, the
cycloalkyl rings may be fused to an additional benzene ring (to
provide fused multiple ring systems such as fluorene). Example of
such benzo fused cycloalkyls include, but are not limited to,
indanyl, 1,2,3,4-tetrahydronaphthalenyl and fluorenyl.
[0092] The term "heteroaryl" refers to an aromatic ring of 5 or 6
members wherein the ring consists of carbon atoms and has at least
one heteroatom member. Suitable heteroatoms include nitrogen,
oxygen or sulfur. In the case of 5 membered rings, the heteroaryl
ring contains one member of nitrogen, oxygen or sulfur and, in
addition, may contain up to three additional nitrogens. In the case
of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 membered ring has
three nitrogens, at most two nitrogen atoms are adjacent.
Optionally, the heteroaryl ring is fused to a benzene ring (benzo
fused heteroaryl), a 5 or 6 membered heteroaryl ring (containing
one of O, S or N and, optionally, one additional nitrogen), a 5 to
7 membered cycloalkyl ring or a 5 to 7 membered heterocyclo ring
(as defined supra but absent the option of a further fused ring).
Examples of heteroaryl groups include, and are not limited to,
furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl;
fused heteroaryl groups include indolyl, isoindolyl, indolinyl,
benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl,
quinolizinyl, quinolinyl, isoquinolinyl, and quinazolinyl.
[0093] The term "arylalkyl" means an alkyl group substituted with
an aryl group (e.g., benzyl and phenethyl). Similarly, the term
"arylalkoxy" indicates an alkoxy-group substituted with an aryl
group (e.g., benzyloxy).
[0094] The term "halogen" refers to fluorine, chlorine, bromine,
and iodine. Substituents that are substituted with multiple
halogens are substituted in a manner that provides compounds which
are stable.
[0095] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl and
alkylamino), it shall be interpreted as including those limitations
given above for "alkyl" and "aryl." Designated numbers of carbon
atoms (e.g., C.sub.1-C.sub.6) shall refer independently to the
number of carbon atoms in an alkyl moiety or to the alkyl portion
of a larger substituent in which alkyl appears as its prefix root.
For alkyl, and alkoxy substituents the designated number of carbon
atoms includes all of the independent member included in the range
specified individually and all the combination of ranges within in
the range specified. For example C.sub.1-6 alkyl would include
methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well
as sub-combinations thereof (e.g., C.sub.1-2, C.sub.1-3, C.sub.1-4,
C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6, C.sub.5-6, C.sub.2-5,
etc.). However, for clarity in the terms "C.sub.9-C.sub.14 benzo
fused cycloalkyl", "C.sub.9-C.sub.14 benzo fused cycloalkenyl",
"C.sub.9-C.sub.14 benzo fused aryl"; C.sub.9-C.sub.14 refers to the
number of carbon atoms both in the benzene ring (6) and the number
of atoms in the ring fused to the benzene ring, but does not
include carbon atoms that may be pendent from these multiple ring
systems. The amount of substituents attached to a moiety
"optionally substituted with one to five substituents" is limited
to that amount of open valences on the moiety available for
substitution.
[0096] In general, under standard nomenclature rules used
throughout this disclosure, the terminal portion of the designated
side chain is described first followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6 alkylamidoC.sub.1-C.sub.6alkyl" substituent
refers to a group of the formula:
##STR00066##
[0097] It is intended that the definition of any substituent or
variable at a particular location in a molecule be independent of
its definitions elsewhere in that molecule. It is understood that
substituents and substitution patterns on the compounds of this
invention can be selected by one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
readily synthesized by techniques known in the art as well as those
methods set forth herein.
[0098] Illustrative of the invention is a composition comprising a
pharmaceutically acceptable, carrier and any of the compounds
described above. Also illustrative of the invention is a
composition made by mixing any of the compounds described above and
a pharmaceutically acceptable carrier. A further illustration of
the invention is a process for making a composition comprising
mixing any of the compounds described above and a pharmaceutically
acceptable carrier. The present invention also provides
compositions comprising one or more compounds of this invention in
association with a pharmaceutically acceptable carrier.
[0099] The compounds of the present invention are useful serine
protease inhibitors (in particular, inhibitors of chymase) useful
for treating inflammatory, and serine protease mediated disorders.
Serine proteases such as chymase produced by mast cells have been
recognized to be involved in a variety of inflammatory and wound
healing events (e.g., angiogenesis, collagen deposition and cell
proliferation). Chymase plays these roles by activating a variety
of pre-existing factors present in the microenvironment surrounding
the mast cells. For example, just to name a few of these
interactions chymase activates SCF, angiotensin I to angiotensin
II, endothelin 1, type 1 procollagen, metalloprotienases, IL-1B,
TGF-.beta., as well as, degrades the extracellular matrix (de
Paulis et al. Int Arch Allerg Immunol 118 (1999) 422-425; Longley
et al. Proc Natl Acad Sci USA 94 (1997) 9017-9021). Consequently,
the release of chymase plays significant role in a variety of
pathological conditions associated with vascular proliferation,
fibrosis, tissue remodeling, inflammation, and the like.
[0100] Some of these, inflammatory and serine protease mediated
disorders include, and are not limited to, allergic rhinitis, viral
rhinitis, asthma, chronic obstructive pulmonary diseases,
bronchitis, pulmonary emphysema, acute lung injury (e.g. adult
(acute) respiratory distress syndrome) psoriasis, arthritis,
reperfusion injury, ischemia, hypertension, hypercardia myocardial
infarction, heart failure damage associated with myocardial
infarction, cardiac hypertrophy, arteriosclerosis, saroidosis,
vascular stenosis or restenosis (e.g., associated with vascular
injury, angioplasty, vascular stents or vascular grafts), pulmonary
fibrosis, kidney fibrosis (e.g., associated with
glomerulonephritis), liver fibrosis, post surgical adhesion
formation, systemic sclerosis, keloid scars rheumatoid arthritis,
bullous pemphigiod and atherosclerosis. Additionally, these
compounds can be used for modulating wound healing and remodeling
(e.g., cardiac hypertrophy) as well as immune modulation. The
utility of the compounds to treat inflammatory and serine protease
mediated disorders is illustrated by the following non-limiting
discussions of the proposed mechanisms of actions of chymase. Other
disorders that can be treated with chymase inhibitors can be
determined according to the procedures described herein and the use
of animal knock-out models and the like.
[0101] As mentioned above, chymase coverts angiotensin I into
angiotensin II, and this activity has been associated with vascular
proliferation. In human vascular extracts only about 8% of
angiotensin II activity is inhibited with an angiotensin converting
enzyme inhibitor (lisinopril) while 95% is inhibited by a chymase
inhibitor. In vein grafts, vascular injury associated with catheter
or balloon injury, chymase induces vascular hyperplasia and
restenosis in dogs (Takai and Miyazaki, 21 (2003) 185-189). This
same mechanism of action would also be expected to apply to
restenosis associated with the use of vascular stents. Pathological
serine protease mediated disorders associated with angiotensin II,
including but not limited to hypertension, hypercardia myocardial
infarction, arteriosclerosis, saroidosis, vascular stenosis or
restenosis (e.g., associated with vascular injury, angioplasty,
vascular stents or vascular grafts), and the like.
[0102] Pathological fibrosis can be associated with the
degeneration of organs (e.g., skin, heart, kidneys or liver) or as
an undesirable outcome of surgery. Preventing the formation of
pathological fibrosis would be beneficial in a variety of diseases.
For example mast cell chymase has been implicated in pulmonary
fibrosis, kidney fibrosis, liver fibrosis, post surgical adhesion
formation, systemic sclerosis, keloid scars, and the like.
[0103] In the heart mast cells have been implicated in cardiac
hypertrophy, which involves both fibrosis and remodeling. Cardiac
hypertrophy develops to preserve its function by normalizing
chamber wall stress. Mast cells have been implicated as being
involved in the development of myocardial fibrosis and systolic
pressure over load induced hypertrophy (Hara et al., J. Exp. Med.
195 (2002) 375-381). The remodeling of the heart associated under
these conditions is believed to involve mast cell chymase, which
activates endothelin 1, matrix metalloproteinases and TGF-.beta..
Chymase inhibitors have been shown to exert favorable
cardioprotective action in a dog model of hypertrophy (Matsumoto et
al., Circulation 107 (2003) 2555-2558).
[0104] In the kidneys mast cell chymase has also been implicated in
pathological fibrosis. For example, glomerulonephritis has also
been reported to involve mast cells (Ehara and Shigematsu, Kidney
Inter. 54 (1998) 1675-1683). The results of this found that mast
cells were one of the constitutive cell types in the interstitium
of IgA nephritis patients and contributed to interstitial fibrosis
resulting in deterioration of renal function. Similarly, liver
fibrosis has been associated with mast cells (Yamashiro et al.,
Virchows Arch. 433 (1998) 471-479). Although, the mechanisms for
fibrosis in the kidney and liver have not been as well defined as
for coronary fibrosis, it is very likely that chymase is operating
through similar signaling pathways to cause fibrosis (especially in
liver fibrosis where fibrosis seem to be occurring more frequently
where mast cells stained positive for chymase).
[0105] Chymase is also involved in the formation of fibrous
adhesions associated with surgery. Chymase inhibitors have been
tested in two different animals models and found to reduce the
number of adhesions (Okamoto et al., J. Surg. Res. 107 (2002)
219-222 and Lucas et al., J. Surg. Res. 65 (1999) 135). It has been
suggested that the prevention of adhesions is associated with
blocking the activation of latent TGF-.beta. by chymase (Yoa et
al., J. Surg. Res. 92 (2000) 40-44).
[0106] Collagen induced arthritic mice show increased numbers of
mast cells and expression of chymase in fibroproliferative
inflammation (Kakizoe et al., Inflamm. Res. 48 (1999) 318-324). In
human rheumatoid arthritis increased mast cell density in the
superficial synovium is associated with the severity of the disease
(Grotis-Graham and McNeil, Arthritis & Rheumatism 40 (1997)
479-489). It was theorized by these authors that chymase and its
ability to activate metalloprotinases plays a significant role in
the rapid functional deterioration observed in rheumatoid
arthritis.
[0107] Mast cell chymase has been implicated in artherosclerosis
via its ability to cleave apolipoprotein B-100 of LDL which
facilitates lipoprotein aggregation and uptake by macrophages
(Paananen et al., J. Biol. Chem. 269 (1994) 2023-2031). Chymase
also degrades apolipoprotein A of HDL, which would reduce
cholesterol efflux and increases lipid deposition (Lindstedt et
al., J. Clin. Invest. 97 (1996) 2174-2182). Thus chymase is
involved in two different pathways to atherosclerosis.
[0108] An embodiment of the invention is a method for treating
inflammatory and serine protease mediated disorders in a subject in
need thereof which comprises administering to the subject a
therapeutically effective amount of any of the compounds or
compositions described above. Also included in the invention is the
use of a compound of Formula (I) for the preparation of a
medicament for treating an inflammatory or serine protease mediated
disorder in a subject in need thereof. The term "treating" as used
herein refers to a method for improving, halting, retarding or
palliating an inflammatory or serine protease mediated disorder in
the subject in need thereof. All such methods of treatment are
intended to be within the scope of the present invention.
[0109] In accordance with the methods of the present invention, the
individual components of the compositions described herein can also
be administered separately at different times during the course of
therapy or concurrently in divided or single combination forms. The
instant invention is therefore to be understood as embracing all
such regimes of simultaneous or alternating treatment and the term
"administering" is to be interpreted accordingly.
[0110] The term "subject" as used herein, refers to an animal
(preferably, a mammal; most preferably, a human) who has been the
object of treatment, observation, or experiment.
[0111] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human, that is being sought by a researcher,
veterinarian, medical doctor, or other clinician, which includes
alleviation of the symptoms of the disease or disorder being
treated.
[0112] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0113] To prepare the compositions of this invention, one or more
compounds of Formula (I) or salt thereof as the active ingredient,
is intimately admixed with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques, which carrier
may take a wide variety of forms depending of the form of
preparation desired for administration (e.g. oral or parenteral).
Suitable pharmaceutically acceptable carriers are well known in the
art. Descriptions of some of these pharmaceutically acceptable
carriers may be found in The Handbook of Pharmaceutical Excipients,
published by the American Pharmaceutical Association and the
Pharmaceutical Society of Great Britain.
[0114] Methods of formulating compositions have been described in
numerous publications such as Pharmaceutical Dosage Forms: Tablets,
Second Edition, Revised and Expanded, Volumes 1-3, edited by
Lieberman et al; Pharmaceutical Dosage Forms: Parenteral
Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical
Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et
al; published by Marcel Dekker, Inc.
[0115] In preparing a composition of the present invention in
liquid dosage form for oral, topical, inhalation/insufflation and
parenteral administration, any of the usual pharmaceutical media or
excipients may be employed. Thus, for liquid dosage forms, such as
suspensions (i.e., colloids, emulsions and dispersions) and
solutions, suitable carriers and additives include but are not
limited to pharmaceutically acceptable wetting agents, dispersants,
flocculation agents, thickeners, pH control agents (i.e., buffers),
osmotic agents, coloring agents, flavors, fragrances, preservatives
(i.e., to control microbial growth, etc.) and a liquid vehicle may
be employed. Not all of the components listed above will be
required for each liquid dosage form.
[0116] In solid oral preparations such as, for example, powders,
granules, capsules, caplets, gelcaps, pills and tablets (each
including immediate release, timed release and sustained release
formulations), suitable carriers and additives include but are not
limited to diluents, granulating agents, lubricants, binders,
glidants, disintegrating agents, and the like. Because of their
ease of administration, tablets and capsules represent the most
advantageous oral dosage unit form, in which case solid
pharmaceutical carriers are obviously employed. If desired, tablets
may be sugar coated, gelatin coated, film coated or enteric coated
by standard techniques.
[0117] Preferably these compositions are in unit dosage forms from
such as tablets, pills, capsules, powders, granules, lozenges,
sterile parenteral solutions or suspensions, metered aerosol or
liquid sprays, drops, ampoules, autoinjector devices or
suppositories for administration by oral, intranasal, sublingual,
intraocular, transdermal, parenteral, rectal, vaginal, inhalation
or insufflation means. Alternatively, the composition may be
presented in a form suitable for once-weekly or once-monthly
administration; for example, an insoluble salt of the active
compound, such as the decanoate salt, may be adapted to provide a
depot preparation for intramuscular injection.
[0118] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical carrier,
e.g., conventional tabletting ingredients such as diluents,
binders, adhesives, disintegrants, lubricants, antiadherents, and
glidants. Suitable diluents include, but are not limited to, starch
(i.e., corn, wheat, or potato starch, which may be hydrolized),
lactose (granulated, spray dried or anhydrous), sucrose,
sucrose-based diluents (confectioner's sugar; sucrose plus about 7
to 10 weight percent invert sugar; sucrose plus about 3 weight
percent modified dextrins; sucrose plus invert sugar, about 4
weight percent invert sugar, about 0.1 to 0.2 weight percent
cornstarch and magnesium stearate), dextrose, inositol, mannitol,
sorbitol, microcrystalline cellulose (i.e., AVICEL.TM.
microcrystalline cellulose available from FMC Corp.), dicalcium
phosphate, calcium sulfate dihydrate, calcium lactate trihydrate,
and the like. Suitable binders and adhesives include, but are not
limited to accacia gum, guar gum, tragacanth gum, sucrose, gelatin,
glucose, starch, and cellulosics (i.e. methylcellulose, sodium
carboxymethyl-cellulose, ethylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose, and the
like), water soluble or dispersible binders (i.e., alginic acid and
salts thereof, magnesium aluminum silicate, hydroxyethylcellulose
(i.e. TYLOSE.TM. available from Hoechst Celanese), polyethylene
glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone,
polymethacrylates and pregelatinized starch), and the like.
Suitable disintegrants include, but are not limited to, starches
(corn, potato, etc.), sodium starch glycolates, pregelatinized
starches, clays (magnesium aluminum silicate), celluloses (such as
crosslinked sodium carboxymethylcellulose and microcrystalline
cellulose), alginates, pregelatinized starches (i.e., corn starch,
etc.), gums (i.e., agar, guar, locust bean, karaya, pectin, and
tragacanth gum), cross-linked polyvinylpyrrolidone, and the like.
Suitable lubricants and antiadherents include, but are not limited
to, stearates (magnesium, calcium and sodium), stearic acid, talc
waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax
4000, carbowax 6000, sodium oleate, sodium benzoate, sodium
acetate, sodium lauryl sulfate, magnesium lauryl sulfate, and the
like. Suitable gildants include, but are not limited to, talc,
cornstarch, silica (i.e., CAB-O-SIL.TM. silica available from
Cabot, SYLOID.TM. silica available from W.R. Grace/Davison, and
AEROSIL.TM. silica available from Degussa), and the like.
Sweeteners and flavorants may be added to chewable solid dosage
forms to improve the palatability of the oral dosage form.
Additionally, colorants and coatings may be added or applied to the
solid dosage form for ease of identification of the drug or for
aesthetic purposes. These carriers are formulated with the
pharmaceutical active to provide an accurate, appropriate dose of
the pharmaceutical active with a therapeutic release profile.
[0119] Generally these carriers are mixed with the pharmaceutical
active to form a solid preformulation composition containing a
homogeneous mixture of the pharmaceutical active of the present
invention, or a pharmaceutically acceptable salt thereof. Generally
the preformulation will be formed by one of three common methods:
(a) wet granulation, (b) dry granulation, and (c) dry blending.
When referring to these preformulation compositions as homogeneous,
it is meant that the active ingredient is dispersed evenly
throughout the composition so that the composition may be readily
subdivided into equally effective dosage forms such as tablets,
pills and capsules. This solid preformulation composition is then
subdivided into unit dosage forms of the type described above
containing from about 0.01 mg to about 500 mg of the active
ingredient of the present invention. The tablets or pills
containing the novel compositions may also be formulated in
multilayer tablets or pills to provide a sustained or provide
dual-release products. For example, a dual release tablet or pill
can comprise an inner dosage and an outer dosage component, the
latter being in the form of an envelope over the former. The two
components can be separated by an enteric layer, which serves to
resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in
release. A variety of materials can be used for such enteric layers
or coatings, such materials including a number of polymeric
materials such as shellac, cellulose acetate, cellulose acetate
phthalate, polyvinyl acetate phthalate, hydroxypropyl
methylcellulose phthalate, hydroxy-propyl methylcellulose acetate
succinate, methacrylate and ethylacrylate copolymers, and the like.
Sustained release tablets may also be made by film coating or wet
granulation using slightly soluble or insoluble substances in
solution (which for a wet granulation acts as the binding agents)
or low melting solids a molten form (which in a wet granulation may
incorporate the active ingredient). These materials include natural
and synthetic polymers waxes, hydrogenated oils, fatty acids and
alcohols (i.e., beeswax, carnauba wax, cetyl alcohol, cetylstearyl
alcohol, and the like), esters of fatty acids metallic soaps, and
other acceptable materials that can be used to granulate, coat,
entrap or otherwise limit the solubility of an active ingredient to
achieve a prolonged or sustained release product.
[0120] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, but are not limited to aqueous solutions,
suitably flavored syrups, aqueous or oil suspensions, and flavored
emulsions with edible oils such as cottonseed oil, sesame oil,
coconut oil or peanut oil, as well as elixirs and similar
pharmaceutical vehicles. Suitable suspending agents for aqueous
suspensions, include synthetic and natural gums such as, acacia,
agar, alginate (i.e., propylene alginate, sodium alginate, and the
like), guar, karaya, locust bean, pectin, tragacanth, and xanthan
gum, cellulosics such as sodium carboxymethylcellulose,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropyl cellulose and hydroxypropyl methylcellulose, and
combinations thereof, synthetic polymers such as polyvinyl
pyrrolidone, carbomer (i.e., carboxypolymethylene), and
polyethylene glycol; clays such as bentonite, hectorite,
attapulgite or sepiolite; and other pharmaceutically acceptable
suspending agents such as lecithin, gelatin, or the like. Suitable
surfactants include but are not limited to sodium docusate, sodium
lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate
20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188,
polyoxamer 235, and combinations thereof. Suitable deflocculating
or dispersing agent include pharmaceutical grade lecithins.
Suitable flocculating agent include but are not limited to simple
neutral electrolytes (i.e., sodium chloride, potassium, chloride,
and the like), highly charged insoluble polymers and
polyelectrolyte species, water soluble divalent or trivalent ions
(i.e., calcium salts, alums or sulfates, citrates and phosphates
(which can be used jointly in formulations as pH buffers and
flocculating agents). Suitable preservatives include but are not
limited to parabens (i.e., methyl, ethyl, n-propyl and n-butyl),
sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol,
benzoic acid, chlorhexidine gluconate, phenylethanol, and the like.
There are many liquid vehicles that may be used in liquid
pharmaceutical dosage forms, however, the liquid vehicle that is
used in a particular dosage form must be compatible with the
suspending agent(s). For example, nonpolar liquid vehicles such as
fatty esters and oils liquid vehicles are best used with suspending
agents such as low HLB (Hydrophile-Lipophile Balance) surfactants,
stearalkonium hectorite, water insoluble resins, water insoluble
film forming polymers, and the like. Conversely, polar liquids such
as water, alcohols, polyols and glycols are best used with
suspending agents such as higher HLB surfactants, clays silicates,
gums, water soluble cellulosics, water soluble polymers, and the
like. For parenteral administration, sterile suspensions and
solutions are desired. Liquid forms useful for parenteral
administration include sterile solutions, emulsions and
suspensions. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is
desired.
[0121] Furthermore, compounds of the present invention can be
administered in an intranasal dosage form via topical use of
suitable intranasal vehicles or via transdermal skin patches, the
composition of which are well-known to those of ordinary skill in
that art. To be administered in the form of a transdermal delivery
system, the administration of a therapeutic dose will, of course,
be continuous rather than intermittent throughout the dosage
regimen.
[0122] Compounds of the present invention can also be administered
in a form suitable for intranasal or inhalation therapy. For such
therapy, compounds of the present invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped or as an aerosol spray from a
pressurized container or a nebulizer (such as, a metered dose
inhaler, a dry powder inhaler or other conventional or
non-conventional modes or devices for inhalation delivery) using a
suitable propellant (such as, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas). In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. The pressurized container or nebulizer may contain
a solution or suspension of the active compound. Capsules and
cartridges (such as, those made from gelatin) for use in an inhaler
or insufflator may be formulated containing a powder mix of a
compound of the invention and a suitable powder base such as
lactose or starch.
[0123] Compounds of the present invention can also be administered
in the form of liposome delivery systems, such as small unilamellar
vesicles, large unilamellar vesicles, multilamellar vesicles and
the like. Liposomes can be formed from a variety of phospholipids,
such as cholesterol, stearylamine, phosphatidylcholines, and the
like.
[0124] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include, but are not limited to
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamidephenol,
polyhydroxy-ethylaspartamidephenol, and polyethyl
eneoxidepolylysine substituted with palmitoyl residue. Furthermore,
the compounds of the present invention may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, to homopolymers and copolymers (which means
polymers containing two or more chemically distinguishable
repeating units) of lactide (which includes lactic acid d-, l- and
meso lactide), glycolide (including glycolic acid),
.epsilon.-caprolactone, p-dioxanone (1,4-dioxan-2-one),
trimethylene carbonate (1,3-dioxan-2-one), alkyl derivatives of
trimethylene carbonate, .delta.-valerolactone,
.beta.-butyrolactone, .gamma.-butyrolactone, .epsilon.-decalactone,
hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one (including its
dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione),
1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates, and
cross-linked or amphipathic block copolymers of hydrogels and
blends thereof.
[0125] The therapeutically effective amount of a compound or
composition thereof ray be from about 0.001 mg/kg/dose to about 30
mg/kg/dose. Preferably; the therapeutically effective amount may be
from about 0.001 mg/kg/dose to about 100 mg/kg/dose. More
preferably, the therapeutically effective amount may be from about
0.001 mg/kg/dose to about 50 mg/kg/dose. Most preferably, the
therapeutically effective amount may be from about 0.001 mg/kg/dose
to about 30 mg/kg/dose. Therefore, the therapeutically effective
amount of the active ingredient contained per dosage unit (e.g.,
tablet, capsule, powder, injection, suppository, teaspoonful, and
the like) as described herein will be in the range of from about 1
mg/day to about 21,000 mg/day for a subject, for example, having an
average weight of 70 kg. For oral administration, the compositions
are preferably provided in the form of tablets containing, 0.01,
0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,
200, 250 and 500 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the subject to be
treated.
[0126] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, and the advancement of the disease condition. In
addition, factors associated with the particular subject being
treated, including subject age, weight, diet and time of
administration, will result in the need to adjust the dose to an
appropriate therapeutic level. Advantageously, compounds of the
present invention may be administered in a single daily dose or the
total daily dosage may be administered in divided doses of two,
three or four times daily.
[0127] Representative IUPAC names for the compounds of the present
invention were derived using the ACD/LABS SOFTWARE.TM. Index Name
Pro Version 4.5 nomenclature software program provided by Advanced
Chemistry Development, Inc., Toronto, Ontario, Canada or AutoNom
Version 2.1 provided by Beilstein Informationssysteme.
[0128] Abbreviations used in the instant specification,
particularly the Schemes and Examples, are as follows:
TABLE-US-00006 Boc = tert-butoxycarbonyl BOC-ON =
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile BuLi =
n-butyllithium t-BuOH = tert-butanol Cpd or Cpd = compound d =
day/days DCC = dicyclohexylcarbodiimide DIPEA =
diisopropylethylamine EtOH = ethanol h = hour/hours HOBt =
hydroxybenzotriazole KH = potassium hydride LDA = lithium
diisopropyamide M = molar Mel = methyliodide MeOH = methanol min =
minutes NT = not tested PPA = polyphosphoric acid rt/RT = room
temperature THF = tetrahydrofuran TFA = trifluoroacetic acid TMSBr
= bromotrimethylsilane.
General Synthetic Methods
[0129] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated more particularly in the
schemes that follow. Since the schemes are an illustration, the
invention should not be construed as being limited by the chemical
reactions and conditions expressed. The preparation of the various
starting materials used in the schemes is well within the skill of
persons versed in the art.
[0130] The following schemes describe general synthetic methods
whereby intermediate and target compounds of the present invention
may be prepared. Additional representative compounds and
stereoisomers, racemic mixtures, diasteromers and enantiomers
thereof can be synthesized using the intermediates prepared in
accordance to the general schemes and other materials, compounds
and reagents known to those skilled in the art. All such compounds,
stereoisomers, racemic mixtures, diasteromers and enantiomers
thereof are intended to be encompassed within the scope of the
present invention. Since the scheme is an illustration, the
invention should not be construed as being limited by the chemical
reactions and conditions expressed. The preparation of the various
starting materials used in the scheme is well within the skill of
persons versed in the art.
[0131] Scheme A illustrates the general method for the preparation
of compounds of the present invention by the reaction of a
phosphonate or phosphinate anion (prepared from its corresponding
phosphonate or phosphinate Compound A2 and an organometallic base
such as n-butyllithium) to isocyanate A1 in a solvent such as THF
to afford an amidophosphonate or amidophosphinate compound A3. One
versed in the art will recognize that conventional chemical
transformations may be utilized to prepare certain R.sup.2 and
R.sup.3 substituents of the present invention. For example, for the
preparation of a compound wherein R.sup.3 is amino, a nitro group
may be reduced with hydrazine hydrate in the presence of a
palladium catalyst; or, for the preparation of a compound wherein
R.sup.3 is ureido, a compound in which R.sup.3 is an amino group
may be reacted with a cyanate salt or the like.
[0132] Compound A2, wherein R.sup.5 and R.sup.6 are as previously
defined, may be made according to known methods (Katritsky et. al.
Org. Prep. Proced. Int., 1990, 22(2), 209-213; J. Am. Chem. Soc.,
2002, 124, 9386-9387; and Chem. Ber., 1963, 96, 3184-3194).
Fluorinated R.sup.6 compounds can be made following methods known
in the art such as the methods similar those set forth in
Garabadzhia et al., Journal General Chemistry USSR, English
translation, 1981, pages 1905-1910. Compound A3 may be dealkylated
with bromotrimethylsilane in a solvent such as pyridine, followed
by treatment with dilute HCl to afford Compound A4.
##STR00067##
[0133] Compound A2, wherein Z is a heteroaryl or aryl ring, may be
prepared from a commercially available or known haloalkyl
substituted heteroaryl ring. Another method for preparing Compound
A2 uses a quaternary ammonium salt rather than an alkyl halide.
##STR00068##
[0134] Scheme B shows a method for preparing Compound A2 wherein
R.sup.6 is an alkyl or alkenyl substituent using methods described
in the literature (J. Organomet. Chem. 2002, 643-644, 154-163; J.
Amer. Chem. Soc. 2002, 124, 9386-9387). An alternate method for
preparing such compounds is described in the literature (Med. Chem.
1995, 38(17), 3297-3312; Bioorg. Med. Chem. 1999, 7,
2697-2704).
##STR00069##
[0135] Scheme C illustrates a general method for the preparation of
compounds of the present invention wherein ring system A of Formula
(I) is an aryl substituent and n of Formula (I) is equal to 1.
Reaction of an .alpha./.beta.-unsaturated carboxylic acid, Compound
C3, with phosphorazidic acid dialkyl ester Compound C4 provides
Compound C5. Compound C5 may subsequently undergo a Curtius
rearrangement to afford an isocyanate intermediate, Compound C6.
Compound C6 may be treated with a phosphonate or phosphinate anion
(as previously described in Scheme A) in an aprotic solvent such as
THF to yield amidophosphonate or amidophosphinate Compound C7.
Compound C7 may be dealkylated with bromotrimethylsilane, followed
by treatment with dilute HCl to afford Compound C8.
##STR00070##
[0136] Scheme D further illustrates the preparation of compounds of
the present invention wherein Y of Formula (I) is a heteroaryl
substituent. Compound D1 may be dissolved in an aprotic solvent,
treated with an organometallic base such as n-BuLi, and
subsequently reacted with isocyanate Compound A1 to afford Compound
D2. Compound D2 may undergo a cycloaddition reaction with sodium
azide to provide Compound D3.
##STR00071##
[0137] Scheme E shows the preparation of compounds of the present
invention wherein Y of Formula (I) is a sulfonic acid. Compound B2
may be treated with sodium sulfite to afford Compound E2. Compound
E2 may then be treated with an organometallic base such as
isopropylmagnesium bromide and reacted with isocyanate Compound A1
to yield Compound E3.
##STR00072##
[0138] Scheme F illustrates the preparation of compounds of the
present invention wherein Y of Formula (I) is a carboxylic acid.
Compound F1 may be reacted with isobutylene under acidic conditions
to provide ester Compound F3. Compound F3 may then be treated with
a strong base such as lithium diethylamide and further reacted with
isocyanate Compound A1 to give Compound F4. Compound F4 is
converted into its corresponding carboxylic acid Compound F5 by
treatment with TFA.
##STR00073##
[0139] Scheme G illustrates the preparation of compounds of the
present invention wherein Y of Formula (I) is a carbamate. Compound
G1 may be prepared by the methods described in the literature (J.
Med. Chem. 1989, 32(12), 2548-2554, J. Het. Chem. 1998, 25, 1271).
Compound G1 may be converted to Compound G2 by the method described
in the literature (Eur. J. Med. Chem. 2001, 36(1), 55-62). Compound
G2 may be oxidized using selenium dioxide to yield resultant
carboxylic acid Compound G3. Compound G3 may be coupled with amine
Compound G4 in the presence of an appropriate coupling agent, base,
activating agent, and solvent to afford amide Compound G5. In the
present invention, Compound G3 is coupled to Compound G4 in the
presence of DCC and HOBt to form Compound G5. Compound G5 may be
reduced in the presence of a hydride source such as sodium
borohydride to give alcohol Compound G6, which may be treated with
isocyanate Compound G7 to form Compound G8. Compound G8 may be
deprotected in the presence of t-butyl alcohol and potassium
carbonate to yield carbamate Compound G9.
##STR00074##
[0140] Scheme H illustrates the preparation of compounds of the
present invention wherein Y of Formula (I) is hydroxymethyl.
Nitrile Compound D2 may be converted to an imidate in the presence
of HCl gas, followed by hydrolysis to yield Compound H1. Compound
H1 may be reduced to a primary alcohol in the presence of hydride
source, such as sodium borohydride, to give methyl alcohol Compound
H2.
##STR00075##
[0141] Scheme I illustrates the preparation of compounds of the
present invention wherein Y of Formula (I) is a sulfamic acid
methyl group. Compound H2 may be treated with a base such as sodium
hydride, followed by the addition of sulfamoyl chloride to yield
Compound I1.
##STR00076## ##STR00077##
[0142] Scheme J illustrates the general method for the preparation
of compounds of the present invention wherein R.sup.3 is an amide
substituent on ring A as defined by the invention.
Dinitro-substituted Compound J1 may be reduced by hydrogenation in
the presence of a palladium catalyst to give Compound J2 which then
may be acylated with BOC-ON to provide Compound J3.
[0143] Compound J4 may be acylated with acid chloride Compound J5
to yield Compound J6, followed by saponification of Compound J6 to
provide carboxylic acid Compound J7. Compound J8 may be prepared by
coupling Compound J3 to Compound J7 using an appropriate coupling
agent, activating agent, and solvent.
[0144] The Boc protecting group of Compound J8 was removed under
acidic conditions to afford the free amine, Compound J9. Treatment
of Compound A2 with an organometallic base such as n-butyllithium,
followed by reaction with carbon dioxide afforded the carboxylated
phosphonic ester, Compound J10. Compound J10 was converted to its
acid chloride by treatment with thionyl chloride followed by
condensation with amine Compound J9 to afford amide Compound J11.
Compound J11 was dealkylated using bromotrimethylsilane and treated
with HCl to provide Compound J12.
##STR00078##
[0145] Scheme K illustrates a general method for the preparation of
compounds of the present invention wherein Z is an N-substituted
indole as previously defined. Compound K1 may be reacted with an
alkylating agent such as methyl iodide or an arylating agent such
as bromobenzene with copper oxide, Compound K2. Compound K2 may be
treated with N,N-dimethylmethyleneammonium iodide to afford
Compound K3. Compound K3 may be converted to Compound K4 using
methyl iodide, and then reacted with a phosphite or phosphonite to
provide Compound K5. Compound K5 may be reacted with Compound A1
and dealkylated as previously described to yield Compound K6.
[0146] Optionally, the phenyl portion of Compound K2 may be
substituted with an alkoxycarbonyl. In this instance, the ester may
be reduced to its corresponding methyl alcohol, and converted to a
methyl halide using techniques and reagents known to those skilled
in the art. The halide may then be converted to Compound A2 wherein
Z is an indole as previously defined in the present invention.
Compound A2 may be subsequently reacted according to Scheme A to
form a compound of Formula (I) wherein the phosphonic attached
through the aryl portion of indole Z.
##STR00079##
[0147] Scheme L illustrates the general method for the preparation
of compounds of the present invention wherein R.sup.4 is a
heterocyclylcarbonyl substituent. Compound L1 may be made by the
procedures described in JACS 1963, 6, 711-716 and JACS 1971,
93(12), 2897-2904.
[0148] Compound L1 may be reacted with an organometallic base, such
as butyllithium, followed by treatment with
di-tert-butyldicarbonate to give Compound L2. Compound L2 may be
converted to Compound L4 using the methods described previously.
Compound L4 may be deprotected under acidic conditions to afford
Compound L5. The carboxylic acid group of Compound L5 may be
treated with an amine, such as 4-phenylpiperidine, in the presence
of an appropriate coupling agent, base, activating agent, and
solvent. to afford Compound L6. Dealkylation of Compound L6 as
described supra yields Compound L7.
##STR00080## ##STR00081##
[0149] Scheme M illustrates a general method for the preparation of
compounds of the present invention. A Compound M1, wherein R.sup.3
is an alkoxycarbonyl substituent, may be reduced in the presence of
a hydride source to the corresponding alcohol, Compound M2.
Compound M2 may be oxidized to aldehyde Compound M3. Reaction of
Compound M3 with a Wittig reagent affords alkene Compound M4.
Saponification of Compound M4 provides carboxylic acid Compound M5,
which may be coupled with an amine, such as benzyl amine, in the
presence of an appropriate coupling agent as described supra, to
give amide Compound M6. Compound M6 may be dealkylated using the
procedure previously described in Scheme A to yield Compound
M7.
[0150] Alternatively, other compounds of the present invention
wherein R.sup.3 is alkoxy or --C(.dbd.O)NR.sup.11R.sup.12 may be
derived from Compound M2. The hydroxy group of Compound M2 may be
alkylated using reagents and methods known to one skilled in the
art to afford compounds wherein R.sup.3 is alkoxy. Alternatively,
the hydroxy group of Compound M2 may be reacted with a variety of
acylating agents known to one skilled in the art, such as
isocyanates, to arrive at compounds of the present invention
wherein R.sup.3 is a carbamate.
##STR00082##
[0151] As shown in Scheme N, Compound M3 may be reacted with a
variety of amines in the presence of a hydride source under acidic
conditions to yield Compound N1. Dealkylation of Compound N1 by the
method described in Scheme A affords Compound N2.
##STR00083##
[0152] The preparation of compounds of the present invention
wherein R.sup.3 is --C(.dbd.O)Cy as previously defined, and said Cy
is attached through a nitrogen atom, is shown in Scheme P. Compound
M1 may be saponified under basic conditions to provide Compound P1,
which may be treated with thionyl chloride to give Compound P2.
Compound P2 may be reacted with a heterocyclic amine to provide
Compound P3. Dealkylation of Compound P3 using methods previously
described affords Compound P4.
##STR00084##
[0153] Scheme Q illustrates a method for the preparation of
compounds of the present invention wherein R.sup.5 and R.sup.6 are
appropriately substituted alkoxy substituents as defined herein. A
compound of formula Q1 wherein R.sup.5 is hydrogen and R.sup.6 is
hydroxyl may be coupled with an appropriately substituted alcohol
in the presence of MSNT
(1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole) to afford a
compound of formula Q2 wherein R.sup.5 is a substituted alkyl and
R.sup.6 is a substituted alkoxy as defined herein.
[0154] Alternatively, compounds of formula Q1 may be elaborated
using an appropriately substituted alkylating agent to provide
compounds of the present invention where either one or both
hydroxyl groups of the phosphonic acid are alkylated. An alkylating
agent in this instance is an alkyl substituent that is optionally
substituted as defined for R.sup.5 or R.sup.6, and said alkyl
substituent is substituted with a leaving group. A leaving group is
defined as a substituent that is activated toward nucleophilic
displacement, including halides, tosylates, and the like.
##STR00085##
[0155] Scheme R illustrates the preparation of compounds of the
present invention wherein R.sup.5 and R.sup.6 (when R.sup.6 is
alkoxy) are taken together with the atoms to which they are both
attached to form a monocyclic ring. A diol of formula R1 may be
treated with a benzyl- or lower alkyl-dichlorophosphite to form a
cyclic phosphonate of formula R2. A compound of formula R2 may be
condensed under refluxing conditions with a compound of formula B2
to form a compound of formula R3. The elaboration of a compound of
formula R.sup.3 to a compound of formula R4 may be achieved using
the methods described for Scheme A.
SPECIFIC SYNTHETIC EXAMPLES
[0156] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter. The depicted intermediates may also
be used in subsequent examples to produce additional compounds of
the present invention. No attempt has been made to optimize the
yields obtained in any of the reactions. One skilled in the art
would know how to increase such yields through routine variations
in reaction times, temperatures, solvents and/or reagents.
[0157] All chemicals were obtained from commercial suppliers and
used without further purification. .sup.1H and .sup.13C NMR spectra
were recorded on a Bruker AC.RTM. 300B (300 MHz proton) or a Bruker
0 AM-400 (400 MHz proton) spectrometer with Me.sub.4Si as an
internal standard (s=singlet, d=doublet, m=multiplet, t=triplet,
br=broad). ES-MS were recorded on a Micromass.RTM. mass
spectrometer or on an Agilent.RTM. HPLC mass spectrometer. TLC was
performed with Whatman.RTM. 250-.mu.m silica gel plates.
Preparative TLC was performed with Analtech.RTM. tapered silica gel
GF plates. Preparative HPLC separations were carried out on a
Gilson.RTM.HPLC using a Phenomenex.RTM. Kromasil 100A C18 column
(25 cm.times.50 mm, or 10 cm.times.21.2 mm) using gradients of
CH.sub.3CN/water/0.2% TFA; Analytical HPLC separations were carried
out on a Supelco.RTM. ABZ+Plus column (5 cm.times.2.1 mm) or a
YMC.RTM. J'Sphere H80 S4 column (5 cm.times.2 mm) with detection at
220 nm and 254 nm on a Hewlett Packard.RTM. 1100 UV detector. The
gradient used was 10% to 90% CH.sub.3CN/water/0.1% TFA in 6 min.
Reported percent purity data is based on the 220 nm data.
Microanalysis was performed by Robertson Microlit Laboratories,
Inc.
[0158] Representative Chemical Abstracts Service (CAS) Index-like
names for the compounds of the present invention were derived using
the Autonom Version 2.1 nomenclature software.
Example 1
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosp-
honic acid, Cpd 9
[0159] A solution of Compound 1a (5.01 g, 19.2 mmol) and Compound
1b (10 mL) was refluxed for 105 min. The solution was concentrated
under high vacuum at 90.degree. C. to yield 6.01 g of Compound 1c
as a pale yellow viscous oil; HPLC: 3.51 min; MS (ES) m/z 319
(MH.sup.+).
[0160] To a solution of 2.5 M n-BuLi in hexanes (4.73 mL, 12 mmol)
in THF (30 mL) at -78.degree. C. was added dropwise a solution of
Compound 1c (3.77 g, 12 mmol) in THF (30 mL) over 15 min. After
stirring for an additional 30 min, Compound 1d (naphthalen-2-yl
isocyanate) (2.0 g, 12 mmol) in THF (30 mL) was added dropwise to
the mixture over 5 min. After the addition was complete, the
solution was allowed to reach rt and stirred overnight. Excess
saturated NH.sub.4Cl (aq) was added, and the layers were separated.
The aqueous portion was extracted with EtOAc (3.times.20 mL). The
combined organic extracts were dried (Na.sub.2SO.sub.4), filtered,
and concentrated under reduced pressure at rt. The residue was
taken up in CH.sub.3CN (10 mL), the solid was collected and dried
under N.sub.2/vacuum to afford Compound 1e (4.3 g) as a white
powder: HPLC: 4.25 min; MS (ES) m/z 488 (MH.sup.+).
Procedure A: General Method for Deethylation of Phosphonates and
Phosphinates
[0161] To a solution of the phosphonate or phospinate (x mmol) in
pyridine (5 mL/mmol of phosphonate or phosphinate) is added excess
bromotrimethylsilane (5.times. to 8.times.mmol) in three portions
at 15 min intervals. The mixture is stirred for 60 min after the
last addition, then concentrated under reduced pressure. The
residue is stirred with excess 1N HCl (aq) for 60 min. The white
precipitate is collected and rinsed sequentially with 1N HCl (aq)
and water, then dried under N.sub.2/vacuum. The crude product may
be purified by trituration with appropriate solvents, salt
formation, recrystallization, or reverse phase chromatography.
[0162] Compound 1e (4.3 g, 8.8 mmol) was deethylated according to
Procedure A. The crude product was further purified: the white
solid was stirred with CH.sub.3CN for 60 min, collected, rinsed
with CH.sub.3CN, and dried under N.sub.2/vacuum to afford 3.2 g of
Cpd 9 as a white powder: HPLC 4.47 min; MS (ES) m/z 432
(MH.sup.+).
[0163] To a solution of Cpd 9 (2.68 g, 6.2 mmol) in CH.sub.3OH (10
mL) was added a solution of tris(hydroxymethyl)aminomethane (10.5
g, 12.4 mmol) in CH.sub.3OH (10 mL). The solution was concentrated,
and the resulting white solid was recrystallized from i-PrOH to
yield 4.0 g of the tromethamine salt of Cpd 9 as an off-white
solid. HPLC: 4.4 min, 94%; MS (ES) m/z (MH.sup.+)=432; .sup.1H NMR
(DMSO-d.sub.6) .delta. 3.32 (s, 10H), 4.59 (d, 1H), 7.30-7.42
(overlapping m, 3H), 7.56 (d, 1H), 7.71-7.80 (overlapping m, 3H),
7.94-7.05 (overlapping m, 3H), 8.28 (s, 1H), 11.40 (s, 1H); Anal.
Calc'd for C.sub.20H.sub.15NO.sub.4PSCl.1.6
C.sub.4H.sub.11NO.sub.3.1.0 i-PrOH.0.25H.sub.2O: C, 51.16; H, 6.01;
N, 5.28; H.sub.2O, 0.66. Found: C, 51.21; H, 5.92; N, 5.22;
H.sub.2O, 0.74.
##STR00086##
[0164] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure for Example 1,
the following compounds were prepared without further
purification:
TABLE-US-00007 Cpd MS (MH.sup.+) Cpd MS (MH.sup.+) 30 439 76 476 31
392 82 382 55 436 (MH-) 96 393 57 393 106 430 59 398 129 381 64 398
135 386 67 510 (MH-) 137 393 68 379 (MH-) 138 434 79 393
Example 2
[(Benzo[b]thiophen-2-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosphonic
acid, Cpd 140
[0165] To a solution of Compound 2a (3.5 g, 26.1 mmol) in 25 mL of
THF at -78.degree. C. was added a solution of 2.5 M n-BuLi in
hexanes (13 mL, 32.6 mmol). The reaction was warmed to 0.degree. C.
and stirred for 25 min, then 4 mL of DMF was added slowly. The
solution was heated to reflux for 1 h. The reaction was cooled to
rt, poured into water and extracted three times with Et.sub.2O. The
combined organic extracts were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt. The crude oil was dissolved in 25 mL of MeOH,
cooled to 0.degree. C., and NaBH.sub.4 (1.6 g, 42 mmol) was added
and stirred for 2 h. After quenching with excess acetone, the
mixture was concentrated, and the residue was partitioned between
EtOAc and brine. The brine was extracted twice with EtOAc, and the
combined organic extracts were washed twice with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure at rt. The crude solid was stirred with 6:1
CH.sub.2Cl.sub.2/hexane, then collected to afford Compound 2b (2.52
g) as an off-white powder: HPLC: 2.85 min.
[0166] To Compound 2b (2.52 g, 16.8 mmol) was added 10 mL of
thionyl chloride and refluxed for 1.5 h. The reaction was
concentrated under reduced pressure at rt, and the residue was
treated with hexanes. After concentration, the residue was treated
with excess triethylphosphite Compound 1b and refluxed for 1.5 h.
The reaction was concentrated under reduced pressure at 90.degree.
C. and purified by flash column chromatography (silica, 0 to 40%
EtOAc/Hexane) to yield Compound 2c (2.5 g) as an oil: HPLC: 3.32
min; MS (ES) m/z 285 (MH.sup.+).
[0167] From Compound 2c (0.64 g, 2.25 mmol) was prepared Compound
140 according to Procedure A: HPLC: 3.87 min; MS (ES) m/z 398
(MH.sup.+).
##STR00087##
Example 3
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylthiocarbamoyl)-methyl]-p-
hosphonic acid, Cpd 45
[0168] Using the procedure described in Example 1 and substituting
2-napthylthioisocyanate for 2-naphthylisocyanate, Compound 45 was
synthesized as a pale yellow powder: HPLC: 4.89 min; MS (ES) m/z
448 (MH.sup.+).
Example 4
[1-(5-Chloro-benzo[b]thiophen-3-yl)-1-(naphthalen-2-ylcarbamoyl)-ethyl]-ph-
osphonic acid, Cpd 125
[0169] To a solution of 2.5 M n-BuLi in hexanes (0.44 mL, 12 mmol)
in THF (7 mL) at -78.degree. C. was added dropwise a solution of
Compound 1c (3.77 g, 1.1 mmol) in THF (7 mL). After stirring for 30
min, methyl iodide (0.068 mL, 1.1 mmol) was added dropwise by
syringe. The reaction was warmed to 0.degree. C. and then to rt.
The solution was returned to -78.degree. C. and a solution of 2.5 M
n-BuLi in hexanes (0.44 mL, 12 mmol) was added dropwise. After
stirring for 30 min, Compound 1d (0.19, 1.1 mmol) in THF (7 mL) was
added dropwise to the mixture. After the addition was complete, the
solution was allowed to reach rt and stirred overnight. Excess
saturated NH.sub.4Cl (aq) was added, and the layers were separated.
The aqueous portion was extracted with EtOAc (3.times.5 mL). The
combined organic extracts were dried (Na.sub.2SO.sub.4), filtered,
and concentrated under reduced pressure at rt. The residue was
dissolved in CH.sub.3CN (5 mL), and filtered. The filtrate was
purified by flash column chromatography (silica, CH.sub.2Cl.sub.2)
to yield Compound 4a (0.036 g) HPLC: 4.62 min; MS (ES) m/z 502
(MH.sup.+).
[0170] Compound 4a was converted to Compound 125 using Procedure A:
HPLC: 4.34 min (94%); MS (ES) m/z 444 (MH.sup.-).
##STR00088##
Example 5
[(5-Chloro-1,1-dioxo-1H-1.lamda..sup.6-benzo[b]thiophen-3-yl)-(naphthalen--
2-ylcarbamoyl)-methyl]-phosphonic acid, Cpd 86
[0171] Compound 1e (0.20 g, 0.41 mmol) was suspended in acetic acid
(5 mL) and heated to 47.5.degree. C. and sodium perborate
tetrahydrate Compound 5a (0.31 g, 2.0 mmol) was added portionwise
over 15 min, and the reaction was stirred at 47.5.degree. C.
overnight. The reaction was partitioned between water and EtOAc,
and the layers were separated. The aqueous phase was extracted with
EtOAc, and the combined organic phases were washed sequentially
with saturated NaHCO.sub.3 (aq), brine, and then dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt. The residue was purified by flash column
chromatography (silica, 0-40% EtOAc/hexane) to yield Compound 5b
(0.052 g): HPLC: 3.87 min; MS (ES) m/z 520 (MH.sup.+).
[0172] Compound 5b (0.052 g, 0.10 mmol) was converted Compound 86
(0.0185 g) by Procedure A: HPLC: 3.25 min, 95%; MS (ES) m/z 462
(MH-).
##STR00089##
Example 6
{[(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl-
]-methyl}-methyl-phosphinic acid, Cpd 17
[0173] A solution of Compound 1a (1.96 g, 7.48 mmol) in excess
diethylmethylphosphonite was refluxed for 3 h. The solution was
concentrated under high vacuum at 90.degree. C., and the residue
was purified by flash column chromatography (silica, 0-100%
EtOAc/hexanes) to yield 1.88 g of Compound 6a as a slightly cloudy
pale yellow viscous oil: HPLC: 3.19 min; MS (ES) m/z 290
(MH.sup.+).
[0174] To a suspension of Compound 6b (5.0 g, 27.2 mmol) in dry
benzene (20 mL) was added triethylamine (3.74 mL, 27.2 mmol). The
solution cooled to 0.degree. C., and Compound 6c (5.86 mL, 27.2
mmol) was added rapidly dropwise, and the cooling was removed. The
reaction was stirred 18 h, then poured into H.sub.2O. The mixture
was extracted three times with EtOAc, and the combined organic
extracts were washed once with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure at rt. The
residue was purified by flash column chromatography (silica, 0-100%
EtOAc/hexanes) to yield 4.88 g of Compound 6d as a white solid:
HPLC: 3.65 min.
[0175] Compound 6d (3.4 g, 16.3 mmol) was dissolved in benzene (30
mL) and refluxed for 3 h. The solution was concentrated under
reduced pressure at rt and the resulting crude Compound 6e was used
without purification in the next reaction.
[0176] To a solution of 2.5M n-BuLi in hexanes (8.9 mL, 22.3 mmol)
in THF (30 mL) at -78.degree. C. was added dropwise a solution of
Compound 6a (4.7 g, 16.3 mmol) in THF (30 mL) over 15 min. After
stirring for an additional 30 min, a solution of Compound 6d (3.4
g, 16.3 mmol) in THF (30 mL) was added dropwise to the mixture over
5 min. After the addition was complete, the solution was stirred at
-78.degree. C. for 30 min, then quenched cold with excess
NH.sub.4Cl (saturated, aq.), and stirred overnight at rt. The
layers were separated, and the aqueous portion was extracted with
EtOAc (2.times.20 mL). The combined organic extracts were washed
once with brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure at rt. The residue was purified
by flash column chromatography (silica, 0-50% EtOAc/hexanes) to
yield 4.1 g of a pale yellow solid, which was stirred with 15 mL
CH.sub.3CN, collected, and dried under N.sub.2/vacuum to afford 3.5
g of Compound 6f as a white powder: HPLC: 4.04 min., 97%, broad; MS
(ES) m/z 470 (MH.sup.+).
[0177] Compound 6f (3.5 g, 7.46 mmol) was deethylated following
Procedure A. The solid was further purified by taking it up in
MeOH, followed by collection of the precipitate to afford Compound
17 (2.93 g) as a white powder: HPLC 4.0 min.
[0178] To a mixture of Compound 17 (2.93 g, 6.2 mmol) in CH.sub.3OH
(10 mL) was added a solution of tris(hydroxymethyl)aminomethane
(0.75 g, 6.2 mmol) in CH.sub.3OH (10 mL). The solution was filtered
and concentrated under reduced pressure at rt, and the resulting
white solid was recrystallized from CH.sub.3CN/EtOAc to yield the
tromethamine salt of Compound 17 (3.35 g) as a white solid. HPLC:
4.02 min, 100%; MS (ES) 442 (MH.sup.+); .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.07 (d, 3H), 3.45 (s, 6H), 4.48 (d, 1H), 6.12 (d, 1H),
7.12-7.18 (br m, 1H), 7.24-7.45 (overlapping m, 4H), 7.92-8.00
(overlapping m, 3H), 10.92 (d, 1H); Anal. Calc'd for
C.sub.19H.sub.15NO.sub.3PSCl F.sub.2.1.0
C.sub.4H.sub.11NO.sub.3.0.15H.sub.2O: C, 48.84; H, 4.69; N, 4.96;
H.sub.2O, 0.48. Found: C, 48.99; H, 4.62; N, 4.97; H.sub.2O,
0.42.
##STR00090##
[0179] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 6,
the following compounds were prepared without further
purification:
TABLE-US-00008 Cpd MS (MH.sup.+) 14 406 15 422 (MH-) 16 460 20 430
21 422 (MH-) 24 422 (MH-) 28 444 29 456 33 389 66 422 (MH-) 144 382
145 436 146 420 147 451 148 464 150 407 152 474 153 490 154 436 155
420 156 442 157 431 160 440 161 440 162 442 163 442 164 485 165 466
166 451 167 485 168 464 (MH-) 169 442 170 475 171 442
[0180] The following compounds can be made by those skilled in the
art by using Example 6 and varying the starting materials,
reagent(s) and conditions used: compounds 300, 301, 302, 303, 304,
305, 306, and 307.
Example 7
[(5-Chloro-benzo[b]thiophen-3-yl)-(2-amino-4-benzothioazol-6-ylcarbamoyl)--
methyl]-phosphonic acid, Cpd 69
[0181] Using the procedure described in Example 6 for the
conversion of Compound 6b to Compound 17, Compound 7a was converted
to Compound 7b. Compound 7b was suspended in a small volume of
1,4-dioxane and gaseous HCl was bubbled in to yield a clear yellow
solution and the solution was stirred for 1 h. The reaction was
concentrated under reduced pressure at rt, the residue stirred with
1N HCl (aq) for 45 min, and the solid was collected to yield
Compound 69 as a yellow powder: HPLC: 2.58 min; MS (ES) m/z 454
(MH.sup.+).
##STR00091##
Example 8
2-(5-Chloro-benzo[b]thiophen-3-yl)-n-naphthalen-2-yl-2-(1
h-tetrazol-5-yl)-acetamide, Cpd 88
[0182] A solution of Compound 8a (1.15 g, 5.53 mmol) in THF (10 mL)
was added dropwise to a solution of 2.5M n-BuLi in hexanes (2.40
mL, 6.08 mmol) in THF (10 mL) at -78.degree. C. After stirring for
30 min at -78.degree. C., a solution of Compound 1d (0.94 g, 5.60
mmol) in THF (10 mL) was added dropwise. After 1 h, the reaction
was quenched at -78.degree. C. with excess NH.sub.4Cl (aq). After
warming to rt gradually, the layers were separated, and the aqueous
phase was extracted with EtOAc (3.times.10 mL). The combined
organic extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure at rt. The residue was stirred
with MeOH, and the precipitate was collected to yield Compound 8b
(1.5 g) as an off-white powder: HPLC: 4.39 min.
[0183] A suspension of Compound 8b (0.28 g, 0.75 mmol), sodium
azide (0.15 g, 2.24 mmol), and triethylamine hydrochloride (0.31 g,
2.24 mmol) in toluene (7 mL) was refluxed overnight. Upon cooling
to rt, EtOAc (10 mL) and 1 N HCl (10 mL) were added and the mixture
was stirred vigorously. The biphasic mixture was filtered and a tan
solid was collected. The layers were separated, and the organic
layer was concentrated under reduced pressure at rt. The residue
was treated with CH.sub.3CN, and a tan solid was collected. The
combined solids were treated with hot CH.sub.3CN (100 mL), cooled,
and the solid was collected to afford Compound 88: HPLC: 4.11 min;
MS (ES) m/z 420 (MH.sup.+)=420; .sup.1H NMR (DMSO-d.sub.6) .delta.
6.15 (s, 1H), 7.41-7.62 (overlapping m, 4H), 7.82-7.93 (overlapping
m, 5H), 8.10 (d, 1H, J=8.6 Hz), 8.32 (s, 1H), 10.92 (s, 1H).
##STR00092##
Example 9
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-sulfo-
nic acid, Cpd 50
[0184] To a solution of Compound 1a (1.0 g, 3.85 mmol) in acetone
(5 mL) was added a solution of sodium sulfite (0.49 g, 3.85 mmol)
and KI (potassium iodide) (0.13 g, 0.77 mmol) in water (10 mL). The
solution was refluxed for 3.5 h, then cooled to rt and concentrated
under reduced pressure. The residue was treated with 1N HCl (15
mL), filtered, and the filtrate was extracted with EtOAc
(3.times.10 mL). The combined organic extracts were filtered, and
concentrated under reduced pressure at rt to yield 0.60 g of
Compound 9a as a white powder: HPLC: 3.38 min; MS (ES) m/z 261
(MH.sup.-).
[0185] To a suspension of Compound 9a (0.29 g, 1.11 mmol) in THF (7
mL) at -5.degree. C. was added a solution of 2 M i-PrMgBr in
Et.sub.2O (1.39 mL, 2.77 mmol). The mixture was stirred for 2 h at
rt, then cooled to -10.degree. C. before treatment with a solution
of Compound 1d (0.20 g, 1.17 mmol) in THF (7 mL). After stirring
overnight at rt, the reaction was quenched with 3 mL of 1N HCl
(aq), and extracted with EtOAc (3.times.10 mL). The combined
organic layers were washed with brine (10 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt. The resulting tan foam was dissolved in a minimum
volume of CH.sub.3CN and allowed to stand overnight. The solution
was filtered, and the filtrate was concentrated under reduced
pressure and the residue was purified by reverse phase HPLC (20-90%
CH.sub.3CN/H.sub.2O). The resulting white powder was dissolved in
CH.sub.3CN, filtered, and concentrated under reduced pressure at rt
to yield Compound 50 (0.14 g) as a white solid: HPLC: 3.14 min; MS
(ES) m/z 430 (MH.sup.-); .sup.1H NMR (DMSO-d.sub.6) .delta. 5.35
(s, 1H), 7.28-7.51 (overlapping m, 4H), 7.72-7.80 (m, 3H),
7.92-8.05 (overlapping m, 3H), 8.24 (s, 1H), 10.40
##STR00093##
Example 10
{[(5-Chloro-benzo[b]thiophen-3-yl)-[2-(4-amino-phenyl)-vinylcarbamoyl]-met-
hyl}-methyl-phosphonic acid, Cpd 12
[0186] Using the procedure described in Example 6, substituting
p-nitro-cinnamic acid for 3,4-difluorocinnamic acid and
substituting Compound 1c for Compound 6a, Compound 10a was
prepared. To a solution of Compound 10a (0.115 g, 0.226 mmol) in 6
mL of 1:1 EtOH/CH.sub.2Cl.sub.2 was added 10% Pd/C (0.060 g) and
hydrazine hydrate (0.173 mL, 3.35 mmol). After 2 h, the reaction
mixture was filtered, concentrated under reduced pressure at rt,
and the resulting yellow solid was taken up in hot acetonitrile and
filtered. The filtrate was concentrated under reduced pressure at
rt, and the residue was purified by flash column chromatography
(silica, 1% CH.sub.3OH/CH.sub.2Cl.sub.2) to yield Compound 10b
(0.064 g) as a bright yellow solid: HPLC: 2.94 min; MS (ES) m/z 479
(MH.sup.+).
[0187] Compound 10b (0.064 g, 0.134 mmol) was deethylated by
Procedure A to yield Compound 12 (0.036 g) as an orange solid:
HPLC: 2.41 min; MS (ES) m/z 423 (MH.sup.+).
##STR00094##
Example 11
{[(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl-
]-methyl}-methyl-phosphonic acid, Cpd 2
[0188] Using the procedure described in Example 6, substituting
phosphonate Compound 1c (0.75 g, 2.34 mmol) for Compound 6a,
followed by deethylation by Procedure A, Compound 2 (0.116 g) was
prepared as a white solid: HPLC: 3.98 min; MS (ES) m/z 444
(MH.sup.+); Anal. Calc'd for C.sub.18H.sub.13NO.sub.3PSCl
F.sub.2.1.0 C.sub.4H.sub.11NO.sub.3.0.10H.sub.2O
C.sub.4H.sub.11NO.sub.3.0.33 C.sub.2H.sub.6O: C, 46.34; H, 4.43; N,
4.87; H.sub.2O, 1.04. Found: C, 46.47; H, 4.09; N, 4.65; H.sub.2O,
1.34.
##STR00095##
[0189] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 11,
the following compounds were prepared without further
purification:
TABLE-US-00009 Cpd MS (MH.sup.+) 18 407 (MH-) 19 424 (MH-) 25 409
37 368 38 437 42 422 49 468 78 440 81 476 199 442 (MH-)
[0190] The following compounds can be made by those skilled in the
art by using Example 11 and varying the starting materials,
reagent(s) and conditions used: compounds 192, 193, 194, 195, 196,
197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 308,
309, 310, 311, 312, 313, 314, and 315.
Example 12
[0191]
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl-
]-phenyl-phosphinic acid, Cpd 89Compound 12a (0.35 g, 1.17 mmol)
was prepared by the method described in Aust J. Chem. 1983, 36,
2517-2536. Using the procedure described in Example 1 and Procedure
A, substituting Compound 12a for Compound 1c, Compound 89 was
prepared as a white solid: HPLC: 4.19 min; MS (ES) m/z 490
(MH.sup.-).
##STR00096##
Example 13
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-carbo-
xylic acid, Cpd 84
[0192] A stream of isobutylene (g) Compound 13b was introduced into
a suspension of Compound 13a (1.07 g, 4.71 mmol) in acetone (15 mL)
containing H.sub.2SO.sub.4 (0.026 mL, 0.94 mmol). After 40 min, the
cloudy solution was stoppered and stirred overnight. The reaction
was poured into 1N NaOH (aq), and the layers were separated. The
aqueous portion was extracted with CH.sub.2Cl.sub.2 (2.times.10
mL). The combined organic extracts were washed with brine (10 mL),
dried (Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt to yield Compound 13c (1.20 g): HPLC: 4.37 min.
[0193] To a solution of diisopropylamine (0.26 mL, 1.84 mmol) in
THF (7 mL) at -40.degree. C. was added a 2.5M solution of n-BuLi in
hexanes (0.74 mL, 1.84 mmol). The temperature lowered to
-70.degree. C., and a solution of Compound 13c (0.38 g, 1.34 mmol)
in THF (7 mL) was added slowly dropwise. The mixture was stirred
for 30 min, at which time a solution of Compound 1d (0.24 g, 1.41
mmol) in THF (7 mL) was added dropwise. After 45 min the reaction
was quenched with 3 mL of NH.sub.4Cl (aq), then extracted with
EtOAc (2.times.10 mL). The combined organic extracts were washed
with brine (10 mL), dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure at rt. The residue was purified
by flash column chromatography (silica, 0-10% EtOAc/hexanes) to
afford Compound 13d (0.18 g): HPLC: 4.73 min; MS (ES) m/z 452
(MH.sup.+).
[0194] A solution of Compound 13d (0.10 g, 0.22 mmol) in 1 mL of
1:1 CH.sub.2Cl.sub.2/TFA was allowed to stand for 65 min. The
solution was concentrated under reduced pressure at rt and the
residue was held under vacuum at rt overnight. The residue was
dissolved in CH.sub.3CN, filtered and concentrated under reduced
pressure at rt. The residue was triturated from diethyl ether at
rt, and the white solid was collected to yield Compound 84 (0.023
g) as a tan solid: HPLC: 4.16 min; MS (ES) m/z 396 (MH.sup.+);
.sup.1H NMR (DMSO-d.sub.6) .delta. 5.33 (s, 1H), 7.39-7.59
(overlapping m, 4H), 7.82-7.91 (overlapping m, 4H), 8.02-8.08
(overlapping m, 2H), 8.31 (s, 1H), 10.63
##STR00097##
Example 14
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-carba-
mate, Cpd 80
[0195] Compound 14d was prepared from Compound 14a by the methods
described in J. Med. Chem. 1989, 32(12), 2548-2554 and J. Het.
Chem. 1998, 25, 1271: HPLC: 3.95 min.
[0196] Compound 14d was converted to Compound 14e using the method
described in Eur. J. Med. Chem. 2001, 36(1), 55-62). Compound 14e
was oxidized with selenium dioxide to yield Compound 14f using the
method described in British patent 1399089 (1971): HPLC: 3.78 min;
MS (ES) m/z 239 (MH.sup.-).
[0197] To a solution of Compound 14f (2.0 g, 8.22 mmol), Compound
14g (1.18 g, 8.22 mmol), and HOBT (1.11 g, 8.22 mmol) in DMF (15
mL) was added DCC (1.69 g, 8.22 mmol) and the reaction was stirred
for 48 h. The slurry was filtered, and the filtrate concentrated
under high vacuum at rt. The residue was purified by trituration
from boiling CH.sub.3CN to yield Compound 14h (1.41 g) as a bright
yellow powder: HPLC: 4.91 min; MS (ES) m/z 364 (MH.sup.-).
[0198] To a suspension of Compound 14h (1.02 g, 2.79 mmol) in 20 mL
of 1:1 THF/MeOH was added NaBH.sub.4 (0.32 g, 8.42 mmol). The
reaction was stirred for 1 h, then quenched with 1N HCl (5 mL). The
volume was reduced approximately 50% under reduced pressure at rt
and the solution was extracted with EtOAc (2.times.10 mL). The
combined organic extracts were washed with brine (10 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt. The residue was purified by recrystallization from
CH.sub.3CN, to yield Compound 14i (0.70 g): HPLC: 4.18 min; MS (ES)
m/z 368 (MH.sup.+).
[0199] To a suspension of Compound 14i (0.25 g, 0.68 mmol) in
CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C., was added Compound 14j
(0.11 mL, 0.88 mmol). After stirring for 3 h at rt, a white solid
was collected and rinsed with a minimal volume of CH.sub.2Cl.sub.2,
then dried under N.sub.2/vacuum to yield 0.36 g of Compound 14k:
HPLC: 4.56 min; MS (ES) m/z 554 (MH.sup.-).
[0200] A suspension of Compound 14k (0.36 g, 0.65 mmol) in
saturated aqueous K.sub.2CO.sub.3 (6 mL) and t-BuOH (3 mL) was
refluxed for 2 h, then stirred at rt for 24 h. The reaction was
concentrated under reduced pressure at rt, treated with aqueous 1N
HCl (10 mL), and extracted with EtOAc (3.times.10 mL). The combined
organic extracts were washed with brine (10 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt to yield Compound 80 (0.105 g): HPLC: 4.29 min; MS
(ES) m/z 410 (MH.sup.-); .sup.1H NMR (DMSO-d.sub.6) .delta. 6.16
(s, 1H), 7.38-7.49 (overlapping m, 3H), 7.57-7.61 (m, 1H),
7.77-7.86 (overlapping m, 3H), 7.97 (s, 1H), 8.07 (d, 1H, J=8.7
Hz), 8.13 (s, 1H), 8.22 (d, 1H, J=2 Hz), 10.02 (s, 1H).
##STR00098## ##STR00099##
Example 15
2-(5-Chloro-benzo[b]thiophen-3-yl)-3-hydroxy-N-naphthalen-2-yl-propionamid-
e, Cpd 136
[0201] A suspension of Compound 8b (1.23 g, 3.27 mmol) in
1,4-dioxane/methanol (1:1, 50 mL) at -78.degree. C. was saturated
with HCl (g). The mixture was maintained at -20.degree. C.
overnight, then concentrated under vacuum, such that the
temperature remained below 20.degree. C. The residue was
partitioned between EtOAc (10 mL) and water (10 mL). The organic
layer was dried (Na.sub.2SO.sub.4), filtered, and concentrated
under reduced pressure at rt, and the resulting residue was
recrystallized from CH.sub.3CN to afford Compound 15a (1.47 g) as a
white powder: HPLC: 4.31 min.
[0202] To a solution of Compound 15a (0.23 g, 0.56 mmol) in THF (5
mL) was added NaBH.sub.4 (0.043 g, 1.12 mmol), LiCl (0.048 g, 1.12
mmol), and EtOH (10 mL). The reaction was stirred for 90 min, then
quenched with several drops of 1N HCl (aq). The mixture was cooled
to -10.degree. C. and treated with 10 mL of 1N HCl. The mixture was
extracted with EtOAc (4.times.) and the combined organic extracts
were washed with brine (4.times.), dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure at rt to yield a
white solid. The solid was triturated with CH.sub.3CN to yield
Compound 136 (0.14 g) as a snow-white solid: HPLC: 4.11 min; MS
(ES) m/z 382 (MH.sup.+); .sup.1H NMR (DMSO-d.sub.6) .delta.
3.69-3.75 (m, 1H), 4.11-4.19 (m, 1H), 4.33-4.37 (m, 1H), 5.17 (t,
1H, J=5 Hz), 7.37-7.49 (m, 3H), 7.59-7.63 (m, 1H), 7.76 (s, 1H),
7.80-7.88 (m, 3H), 8.05 (d, 1H, J=8 Hz), 8.18 (d, 1H, J=2 Hz), 8.35
(s, 1H), 10.46 (s, 1H).
##STR00100##
Example 16
Sulfamic acid
2-(5-chloro-benzo[b]thiophen-3-yl)-2-(naphthalen-2-ylcarbamoyl)-ethyl
ester, Cpd 120
[0203] To a suspension of 95% NaH (0.017 g, 0.68 mmol) in DMF (2
mL) at 0.degree. C. was added a solution of Compound 136 (0.10 g,
0.26 mmol) in DMF (2 mL) dropwise. The suspension was stirred at
0.degree. C. for 1 h, then sulfamoyl chloride (0.067 g, 0.58 mmol)
was added as a solid. After stirring for 1 h at 0.degree. C., the
mixture was treated with excess sulfamoyl chloride. After stirring
overnight, the reaction was quenched with water and extracted with
EtOAc (3.times.5 mL). The combined organic phases were washed with
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated under
reduced pressure at rt. The residue was purified by flash column
chromatography (silica, 0-40% EtOAc/hexanes) to yield Compound 120
(0.10 g) as a white foam: HPLC: 4.12 min; MS (ES) m/z 461
(MH.sup.+); .sup.1H NMR (DMSO-d.sub.6) .delta. 4.29-4.34 (m, 1H),
4.65-4.75 (m, 2H), 7.39-7.50 (m, 3H), 7.57-7.64 (m, 1H), 7.81-7.90
(m, 4H), 8.09 (d, 1H, J=8.5 Hz), 8.215 (d, 1H, J=2 Hz), 8.34 (s,
1H), 10.55 (s, 1H).
##STR00101##
Example 17
[(4-{[1-(Naphthalene-2-carbonyl)-piperidine-4-carbonyl]-amino}-naphthalen--
2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, Cpd 8
[0204] A solution of Compound 17a (10 g, 45.9 mmol) in MeOH (200
mL) was added to 10% Pd/C and hydrogenated for 3.5 h at 40-50 psi.
The mixture was filtered (Celite) and concentrated under reduced
pressure at rt, and the resulting material was triturated with
EtOAc to yield Compound 17b as a crude black solid. Compound 17b
(1.36 g, approx. 8.61 mmol) was dissolved in DMF (20 mL) and TEA
(1.32 mL, 9.46 mmol). To this solution was added
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, (BOC-ON)
(2.33 g, 9.46 mmol), and the reaction was heated at 55.degree. C.
overnight. The solution was concentrated under reduced pressure at
rt and filtered through a plug of silica gel. The crude product was
stirred with CH.sub.2Cl.sub.2 and filtered to yield 0.18 g of
Compound 17c: HPLC: 2.68 min; MS (ES) m/z 259 (MH.sup.+).
[0205] A solution of ethyl isonipecotamate, Compound 17d (2.04 g,
13.0 mmol), and DIPEA (2.3 mL, 13.0 mmol) in 10 mL of
CH.sub.2Cl.sub.2 was treated with 2-naphthoyl chloride, Compound
17e (2.48 g, 13.0 mmol). After stirring for 1.5 h, the mixture was
sequentially washed with 1N HCl (2.times.10 mL), saturated
Na.sub.2CO.sub.3 (aq) (2.times.10 mL), and brine (10 mL). The
organic phase was dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure at rt. The residue was
dissolved in 1,4-dioxane (41 mL) and treated with a solution of
LiOH H.sub.2O (1.63 g, 39 mmol) in 5 mL of water. After 2 h, the
reaction was concentrated under reduced pressure at rt, and the
residue was acidified with 1N HCl (aq), and extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL). The combined organic extracts
were washed with brine (10 mL), dried (Na.sub.2SO.sub.4), filtered,
and concentrated under reduced pressure at rt to yield 3.57 g of
Compound 17g: HPLC: 2.77 min; MS (ES) m/z 284 (MH.sup.+).
[0206] To a solution of Compound 17c (0.18 g, 0.70 mmol), Compound
17g (0.20 g, 0.70 mmol), and HOBT (0.094 g, 0.70 mmol) in DMF (8
mL) was added DCC (0.14 g, 0.70 mmol) and the reaction was stirred
for 6 d. The mixture was filtered, concentrated under reduced
pressure at rt, and the residue suspended in a minimal volume of
CH.sub.2Cl.sub.2, and filtered again. The clear solution was washed
with 1N KHSO.sub.4 (aq) and the organic phase was filtered and
washed sequentially with saturated Na.sub.2CO.sub.3 (aq) and brine.
The organic phase was then dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure at rt. The residue was purified
by flash column chromatography (silica, 0-3% MeOH/CH.sub.2Cl.sub.2)
to afford Compound 17h (0.20 g, 0.382 mmol). A solution of 17h in
TFA (3 mL) was stirred for 50 min. The mixture was concentrated
under reduced pressure at rt and the residue was suspended in
CH.sub.2Cl.sub.2, washed with saturated Na.sub.2CO.sub.3 (2.times.5
mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure at rt to yield 0.17 g of Compound 17i.
[0207] To 100 mL of THF and 2.5 M n-BuLi (79.2 mL, 0.198 mol) at
-78.degree. C. was added dropwise a solution of Compound 17j (50 g,
0.18 mol). After 30 min, CO.sub.2 was bubbled through the reaction
for 1 h, after which point the mixture was warmed to rt. The ice
bath-cooled mixture was quenched with excess saturated
Na.sub.2CO.sub.3 (aq), and the volatile solvents were removed under
reduced pressure at rt. The resulting solution was washed with
Et.sub.2O (3.times.), acidified with 3N HCl (aq), and extracted
with EtOAc (4.times.). The combined organic extracts were washed
once with water, dried (Na.sub.2SO.sub.4), filtered (Celite), and
concentrated under reduced pressure at rt to yield 32.59 g of
Compound 17k: HPLC: 3.06 min, MS (ES) m/z 323 (MH.sup.+).
[0208] Compound 17k (0.13 g, 0.40 mmol) was stirred with 1 mL of
thionyl chloride for 30 min and the mixture was concentrated under
reduced pressure at rt. The residue was treated with hexanes and
concentrated under reduced pressure at rt again. The residue was
dissolved in THF (5 mL), at -78.degree. C., treated with a solution
of Compound 17i (0.17 g, 0.40 mmol) in pyridine (3.5 mL). The
solution was stirred at rt overnight, then concentrated under
reduced pressure at rt. The residue was taken up in
CH.sub.2Cl.sub.2 (5 mL) and washed sequentially with 1N KHSO.sub.4
(aq), saturated Na.sub.2CO.sub.3 (aq) (3.times.5 mL), and brine (5
mL), dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure at rt. The residue was purified by prep-plate
chromatography (75% EtOAc/hexanes) to yield 0.11 g of Compound 171:
HPLC: 4.02 min; MS (ES) m/z 728 (MH.sup.+).
[0209] Compound 17l was deethylated by Procedure A to yield
Compound 8 (0.063 g): HPLC: 3.91 min. MS (ES) m/z 424
{M-[COCH(1-Naph)P(.dbd.O)(OH).sub.2}; .sup.1H NMR (DMSO-d.sub.6)
.delta. 1.6-2.2 (br overlapping m, 4H), 2.7-3.3 (br overlapping m,
3H), 3.6-4.0 (br m, 1H), 4.45-4.75 (br m, 1H), 5.32 (d, 1H, J=24
Hz), 7.39-7.60 (overlapping m, 8H), 7.79-8.0 (overlapping m, 9H),
8.24 (s, 1H), 8.31 (d, 1H, J=7 Hz), 8.38 (d, 1H, J=10 Hz), 9.95 (s,
1H), 10.6 (s, 1H).
##STR00102## ##STR00103##
Example 18
[(4-Chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phos-
phonic acid, Cpd 63
[0210] To a stirred mixture of 95% sodium hydride (0.35 g, 13.85
mmol) in THF (3 mL) at 0.degree. C. was added a solution of
4-chloroindole Compound 18a (0.35 g, 6.59 mmol) in THF (3 mL), and
the mixture was stirred for 15 min. Methyl iodide (1.03 g, 7.26
mmol) was added and the reaction was stirred overnight. The
reaction was quenched with saturated NaHCO.sub.3 (aq), the
volatiles were removed under reduced pressure at rt, and the
resulting mixture was extracted with EtOAc (3.times.). The combined
organic extracts were washed with brine, dried (Na.sub.2SO.sub.4),
filtered (Celite), and concentrated under reduced pressure at rt to
yield 1.11 g of Compound 18b as an oil: HPLC: 3.37 min, 77%.
[0211] To a stirred suspension of Compound 18b (1.09 g, 6.59 mmol)
in CH.sub.2Cl.sub.2 (10 mL) was added Compound 18c (1.58 g, 8.57
mmol). After stirring overnight, the solid was collected and rinsed
sequentially with CH.sub.2Cl.sub.2 and Et.sub.2O. The solid was
dissolved in 1N NaOH (aq) and extracted with CH.sub.2Cl.sub.2
(3.times.). The combined organic extracts were washed with brine,
dried (Na.sub.2SO.sub.4), filtered (Celite), and concentrated under
reduced pressure at rt to yield 0.95 g Compound 18d as a clear oil:
HPLC: 1.18 min, 97%; MS (ES) m/z 223 (MH.sup.+).
[0212] To a stirred solution of Compound 18b (0.944 g, 4.24 mmol)
in EtOH (10 mL) at 0.degree. C. was added methyl iodide (0.66 g,
4.66 mmol). After stirring at room temperature overnight, a solid
was collected by filtration and rinsed sequentially with EtOH and
Et.sub.2O to yield 1.46 g of Compound 18e as a white solid: HPLC:
1.93 min, 68%.
[0213] A mixture of Compound 18e (1.0 g, 2.74 mmol) in triethyl
phosphite (8 mL) was refluxed overnight and concentrated under high
vacuum at 90.degree. C. The residue was dissolved in EtOAc, washed
with H.sub.2O, dried (Na.sub.2SO.sub.4), filtered (Celite), and
concentrated under reduced pressure at rt. The residue was purified
by flash column chromatography (silica, 0-1% MeOH/CH.sub.2Cl.sub.2)
to yield 0.82 g of Compound 18f as an oil: HPLC: 3.39 min; MS (ES)
m/z 316 (MH.sup.+).
[0214] Using the procedure described in Example 1 for the
conversion of Compound 1c to Compound 9, including deethylation by
Procedure A, Compound 18f was converted to Compound 63.
##STR00104##
[0215] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 18,
the following compounds were prepared without further
purification:
TABLE-US-00010 Cpd MS (MH.sup.+) 3 429 11 413 13 471 (MH-) 22 395
27 497 52 451 (M + Na) 58 429 62 433 (MH-) 65 420 74 425 77 423 116
396
Example 19
{(5-Chloro-1-methyl-1H-indol-3-yl)-[2-(4-fluoro-phenyl)-vinylcarbamoyl]-me-
thyl}-phosphonic acid, Cpd 4
[0216] Using the procedure described in Example 18, substituting
5-chloroindole for 4-chloroindole, Compound 19a was prepared.
[0217] Using the procedure described in Example 11, Compound 4 was
prepared: HPLC: 3.60 min; MS (ES) m/z 423 (MH.sup.+).
##STR00105##
Example 20
[(5-Chloro-1-methyl-1H-indol-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-meth-
yl-phosphinic acid, Cpd 1
[0218] Using the procedure described in Example 18, substituting
5-chloroindole for 4-chloroindole, Compound 20a was prepared.
[0219] Using the procedure described in Example 18, substituting
Compound 20a for Compound 18b, Compound 20b was prepared.
[0220] Using the procedure described in Example 1 followed by
deethylation by Procedure A, Compound 20b was converted to Compound
1: HPLC: 3.77 min, 97%; MS (ES) m/z 427 (MH.sup.+).
##STR00106##
[0221] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 20,
the following compounds were prepared without further
purification:
TABLE-US-00011 Cpd MS (MH.sup.+) 6 419 (MH-) 7 439
Example 21
1-Methyl-3-[(naphthalen-2-ylcarbamoyl)-phosphono-methyl]-1H-indole-5-carbo-
xylic acid, Cpd 56
[0222] Using the procedure described in Example 18, Compound 21a
was prepared. To a solution of 2.5 M n-BuLi in hexanes (0.56 mL,
1.40 mmol) in THF (2 mL) at -78.degree. C. was added dropwise a
solution of Compound 21a (0.27 g, 0.79 mmol) in THF (1 mL). After
stirring for an additional 45 min, Compound 1d (0.15 g, 0.87 mmol)
in THF (1.5 mL) was added dropwise to the mixture. After the
addition was complete, the solution was stirred at -78.degree. C.
for 2 h. The mixture was warmed to rt, excess saturated NaHCO.sub.3
(aq) was added, and the solid was collected by filtration. The
solid was rinsed (THF), and air dried to yield Compound 21b (0.12
g): HPLC: 3.77 min.
[0223] Compound 21b (0.060 g, 0.12 mmol) was deethylated by
Procedure A to yield Compound 56 (0.042 g): HPLC: 3.19 min; MS (ES)
m/z 420 (M-H.sub.2O).
##STR00107##
Example 22
[[5-(4-Fluoro-phenyl)-1-methyl-1H-indol-3-yl]-(naphthalen-2-ylcarbamoyl)-m-
ethyl]-phosphonic acid, Cpd 98
[0224] Compound 22a (0.27 g, 0.75 mmol), prepared by the method of
Synlett Jan. 1994, 93, was methylated as described in Example 18 to
yield 0.27 g of Compound 22b: HPLC: 3.65 min, 96.5%; MS (ES) m/z
362 (MH.sup.+).
[0225] Using the procedure described in Example 1, followed by
deethylation Procedure A, Compound 22b converted to Compound 98:
HPLC: 4.46 min; MS (ES) m/z 487 (MH.sup.-).
##STR00108##
Example 23
[(Naphthalen-2-ylcarbamoyl)-(1-phenyl-1H-indol-3-yl)-methyl]-phosphonic
acid, Cpd 128
[0226] A mixture of Compound 23a (5.0 g, 29 mmol), copper(II) oxide
(4.9 g, 63 mmol), potassium carbonate (5.0 g, 36 mmol), and
bromobenzene (30 mL) was refluxed for 13 h. After cooling to rt,
the mixture was filtered (dicalite) and concentrated under reduced
pressure at rt. The residue was triturated with hexanes to yield
5.2 g of Compound 23b as a brown solid: HPLC: 4.44 min, 93%; MS
(ES) m/z 252 (MH.sup.+).
[0227] To a suspension of lithium aluminum hydride (1.0 g, 26 mmol)
in THF (30 mL) was added Compound 23b (5.2 g, 20 mmol) in THF (25
mL) at 0.degree. C. The reaction was stirred for 1 h, then quenched
at 0.degree. C. with moist Na.sub.2SO.sub.4. The mixture was
diluted with THF and filtered (dicalite). The filtrate was
concentrated under reduced pressure at rt, and the residue was
purified by flash column chromatography (silica, 25% EtOAc/hexanes)
to yield 2.7 g of Compound 23c as a white solid: HPLC: 3.62 min,
99%; MS (ES) m/z 224 (MH.sup.+).
[0228] To a solution of Compound 23c in DMF (15 mL) and CCl.sub.4
(4 mL) at 0.degree. C. was added triphenylphosphine (3.4 g, 13
mmol) and the mixture was stirred at rt overnight. The reaction was
concentrated under reduced pressure at rt, dissolved in EtOAc and
passed through a short plug of silica gel (30% EtOAc/hexanes) to
yield 1.3 g of Compound 23d: HPLC: 4.19 min, 91%; MS (ES) m/z 513
(MH.sup.+).
[0229] Using the procedure described in Example 1, substituting
Compound 23d for Compound 1a, Compound 128 was prepared: HPLC: 4.23
min, 83%; MS (ES) m/z 479 (M+Na).
##STR00109##
Example 24
Methyl-{(naphthalen-2-ylcarbamoyl)-[2-(4-phenyl-piperidine-1-carbonyl)-ben-
zo[b]thiophen-3-yl]-methyl}-phosphinic acid, Cpd 32
[0230] Compound 24a was prepared according to the procedures
described in JACS 1963, 6, 711-716 and JACS 1971, 93(12),
2897-2904.
[0231] To a solution of 2.5 M n-BuLi in hexanes (8.5 mL, 21.2 mmol)
and THF (33 mL) at -78.degree. C. was added dropwise a solution of
Compound 24a (3.52 g, 18.4 mmol) in THF (33 mL). After stirring the
resulting yellow slurry for 45 min, di-tert-butyldicarbonate (4.14
g, 19.0 mmol) in THF (33 mL) was added dropwise to the mixture.
After the addition was complete, the solution was allowed to reach
rt then quenched with 50 mL of saturated NH.sub.4Cl (aq). The
layers were separated, and the aqueous portion was extracted with
EtOAc (2.times.20 mL). The combined organic phases were dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure at rt. The residue was purified by flash column
chromatography (silica, 0 to 75% EtOAc/hexanes) to yield 3.68 g of
Compound 24b: HPLC: 2.74 min, 90%; MS (ES) M/Z (MH.sup.+)=292.
[0232] Using the procedure described in Example 18, substituting
Compound 24b (3.68 g, 12.65 mmol) for Compound 18d, and
diethylmethylphosphonite for triethylphosphite, Compound 24c (3.36
g) was prepared: HPLC: 3.67 min.
[0233] Using the procedure described in Example 1, followed by
deethylation Procedure A, Compound 24c (3.36 g, 9.5 mmol) was
converted to Compound 24d (2.18 g): HPLC: 4.24 min; MS (ES) m/z 524
(MH.sup.+).
[0234] To Compound 24d (2.18 g, 4.17 mmol) was added 5 mL of TFA.
After 50 min, the mixture was concentrated under reduced pressure
at rt and the residue was purified by flash column chromatography
(silica, 0 to 20% MeOH/EtOAc) to yield 0.30 g of Compound 24e:
HPLC: 3.63 min, 91%; MS (ES) m/z 468 (MH.sup.+).
[0235] To a solution of Compound 24e (0.20 g, 0.43 mmol), Compound
24f (0.07 g, 0.45 mmol), and HOBT (0.061 g, 0.45 mmol) in DMF (2
mL) was added DCC (0.093 g, 0.45 mmol). After 1 h, the reaction
mixture was filtered, the residue was suspended in a minimal volume
of CH.sub.2Cl.sub.2 and filtered. The filtrate was washed
sequentially with 1N HCl (2.times.), 10% aqueous Na.sub.2CO.sub.3,
and brine, then dried (Na.sub.2SO.sub.4), filtered, and
concentrated under reduced pressure at rt. The residue was purified
by flash column chromatography (silica, 0-60% EtOAc/heptane) to
yield 0.12 g of Compound 24g: HPLC: 4.44 min; MS (ES) m/z 611
(MH.sup.+).
[0236] Compound 24g (0.12 g, 0.197 mmol) was deethylated by
Procedure A to afford Compound 32 (0.086 g): HPLC: 4.49 min, 92%;
MS (ES) m/z 583 (MH.sup.+).
##STR00110## ##STR00111##
[0237] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 24,
the following compounds were prepared without further
purification:
TABLE-US-00012 Cpd MS (MH.sup.+) 38 611 (MH-) 44 640 (MH-) 50 599
(MH-) 121 438 (MH-) 130 529
Example 25
[(5-Chloro-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-(3-ph-
enyl-propyl)-phosphinic acid, Cpd 36
[0238] Compound 25a was prepared according to the procedures
described in JACS 2002, 124, 9386-9387 and J. Organomet. Chem 2002,
643-644, 154-163.
[0239] To a solution of Compound 25a (0.51 g, 2.58 mmol) in THF (10
mL) at -78.degree. C. was added a solution of 2.5 M n-BuLi in
hexanes (1.29 mL, 3.22 mmol). After stirring for 30 min, a solution
of Compound 1a (0.225 g, 0.86 mmol) in THF (7 mL) was added
dropwise. After 35 min, the reaction was quenched with excess
saturated NH.sub.4Cl (aq), and the layers were separated. The
aqueous layer was extracted with EtOAc (3.times.) and the combined
organic extracts were washed with brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated under reduced pressure at rt. The residue
was purified by flash column chromatography (silica, 0-30%
EtOAc/hexanes) to yield 0.070 g of Compound 25b: HPLC: 3.93 min,
88%; MS (ES) m/z 379 (MH.sup.+).
[0240] Using the procedure described in Example 1 with deethylation
Procedure A, Compound 25b was converted to Compound 36: HPLC: 4.70
min, 90%; MS (ES) m/z 520 (MH.sup.+).
##STR00112##
[0241] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 25,
the following compounds were prepared without further
purification:
TABLE-US-00013 Cpd MS (MH.sup.+) 34 488 39 578 40 582 43 548 (MH-)
48 534 51 548 53 562 (MH-)
Example 26
3-(2-Naphthalen-1-yl-2-phosphono-acetylamino)-naphthalene-2-carboxylic
acid methyl ester, Cpd 75
[0242] Using the procedure described in Example 17, Compound 17k
was converted to Compound 75: HPLC: 4.13 min; MS (ES) m/z 450
(MH.sup.+).
[0243] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 26,
the following compounds were prepared without further
purification:
TABLE-US-00014 Cpd MS (MH.sup.+) 139 478
Example 27
[(3-Benzylcarbamoyloxymethyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-met-
hyl]-phosphonic acid, Cpd 72
[0244] To a suspension of Compound 75 (7.6 g, 15.03 mmol) in THF
(150 mL) at 0.degree. C. was added dropwise a 1M solution of
diisobutyl aluminum hydride in toluene (90 mL) and stirred at rt
overnight. The reaction was cooled to 0.degree. C., quenched with
saturated NH.sub.4Cl (aq), and extracted with EtOAc (2.times.). The
combined organic extracts were filtered (Celite), washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated under
reduced pressure at rt. The residue was purified by flash column
chromatography (0-3% MeOH/CH.sub.2Cl.sub.2). The product was
recrystallized from MeOH to yield Compound 27a (1.85 g) as a
crystalline solid: HPLC: 3.66 min; MS (ES) m/z 478 (MH.sup.+).
[0245] To a solution of Compound 27a (0.30 g, 0.63 mmol) in THF (4
mL) was added triethylamine (28 .mu.l, 0.20 mmol) followed by
benzylisocyanate (0.084 g, 0.63 mmol) in THF (2 mL) dropwise. The
flask was wrapped with foil and stirred at rt for 96 h. Additional
benzylisocyanate (0.042 g, 0.032 mmol) and triethylamine (60 .mu.l,
0.43 mmol) were added and the reaction was stirred for an
additional 48 h. The mixture was concentrated under reduced
pressure at rt and the residue was taken up in CH.sub.2Cl.sub.2 and
washed sequentially with 1N KHSO.sub.4 (aq) (2.times.), brine,
dried (Na.sub.2SO.sub.4), then filtered, and concentrated under
reduced pressure at rt. The residue was purified by flash column
chromatography (silica, 0-3% MeOH/CH.sub.2Cl.sub.2) to yield 0.22 g
of Compound 27b: HPLC: 4.19 min, 95%; MS (ES) m/z 611
(MH.sup.+).
[0246] Compound 27b (0.22 g, 0.36 mmol) was deethylated by
Procedure A to yield Compound 72 (0.16 g): HPLC: 3.80 min; MS (ES)
m/z 555 (MH.sup.+).
##STR00113##
[0247] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 27,
the following compounds were prepared without further
purification:
TABLE-US-00015 Cpd MS (MH.sup.+) 97 541 100 631 (MH-) 108 591
Example 28
{[3-(2-Benzylcarbamoyl-vinyl)-naphthalen-2-ylcarbamoyl]-naphthalen-1-yl-me-
thyl}-phosphonic acid, Cpd 109
[0248] A solution of Compound 27a (3.9 g, 8.1 mmol) in CHCl.sub.3
(50 mL) was treated with activated MnO.sub.2 (7.0 g, 80 mmol) and
stirred for 48 h. The mixture was filtered (Celite), and
concentrated under reduced pressure at rt. The residue was
triturated with Et.sub.2O to obtain 3 g of Compound 28a as a yellow
powder: HPLC: 4.35 min; MS (ES) m/z 476 (MH.sup.+).
[0249] A solution of Compound 28a (1.0 g, 2.0 mmol),
methyl-triphenylphosphoranylidene acetate (1.5 g, 4.5 mmol), and
THF (25 mL) was refluxed for 7 h, then concentrated under reduced
pressure at rt. The residue was purified by flash column
chromatography (silica, 5% MeOH/CH.sub.2Cl.sub.2) to obtain 1.4 g
of Compound 28b: HPLC: 4.33 min; MS (ES) m/z 531 (MH.sup.+).
[0250] To a solution of Compound 28b (1.0 g, 1.89 mmol) in 3:1
dioxane-H.sub.2O (20 mL) was added LiOH (0.18 g, 7.50 mmol) and the
mixture was stirred for 3 h. The layers were separated, and the
aqueous layer was acidified with 3N HCl and extracted repeatedly
with EtOAc. The combined organic extracts were dried
(Na.sub.2SO.sub.4), and filtered. The filtrate was concentrated
under reduced pressure at rt to afford 0.52 g of Compound 28c as a
white foam: HPLC: 3.89 min, 70%; MS (ES) m/z 518 (MH.sup.+).
[0251] A solution of Compound 28c (0.40 g), benzylamine (0.10 g,
0.93 mmol) and HOBt (0.104 g, 0.77 mmol) in DMF (5 mL) was treated
DCC (0.16 g, 0.77 mmol) in DMF (1 mL). The mixture was stirred for
24 h, then filtered (Celite) and concentrated under reduced
pressure at rt. The residue was taken up in CH.sub.2Cl.sub.2 and
washed sequentially with saturated NaHCO.sub.3 (aq), H.sub.2O, 1 N
KHSO.sub.4 (aq) and H.sub.2O, then dried (Na.sub.2SO.sub.4) and
filtered. The residue was purified by flash column chromatography
(silica, 5% MeOH/CH.sub.2Cl.sub.2) to yield 0.22 g of Compound 28d:
MS (ES) m/z 607 (MH.sup.+).
[0252] Compound 28d was deethylated by Procedure A to afford
Compound 109: HPLC: 3.64 min; MS (ES) m/z (MH.sup.+)=551.
##STR00114## ##STR00115##
Example 29
[(3-Cyclohexylaminomethyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl-
]-phosphonic acid, Cpd 70
[0253] To a stirred solution of Compound 28a (0.125 g, 0.263 mmol)
and cyclohexyl amine (0.031 g, 0.316 mmol) in DCE (4 mL) was added
NaB(OAc).sub.3H (0.111 g, 0.526 mmol) and glacial acetic acid
(0.017 g, 0.316 mmol) and the mixture was stirred for 48 h. The
reaction was treated with 3N NaOH, and the layers were separated.
The aqueous layer was extracted with CH.sub.2Cl.sub.2 (3.times.)
and the combined organic extracts were washed with water, dried
(Na.sub.2SO.sub.4), filtered (Celite), and concentrated under
reduced pressure at rt. The residue was treated with 1N HCl (aq),
and the solid was collected, rinsed with water, and air-dried. The
product was dissolved in CH.sub.3CN, precipitated with Et.sub.2O,
and the solid was collected and rinsed with Et.sub.2O to yield
0.084 g of Compound 29a: HPLC: 3.27 min; MS (ES) m/z 559
(MH.sup.+).
[0254] From Compound 29a (0.079 g) was prepared Compound 70 by
deethylation Procedure A. The crude product was dissolved in 1:1
CH.sub.2Cl.sub.2/TFA and concentrated. The residue was stirred with
Et.sub.2O, and the solid was collected and rinsed with Et.sub.2O to
yield Compound 70 (0.046 g): HPLC: 2.91 min; MS (ES) m/z 503
(MH.sup.+).
##STR00116##
[0255] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 29,
the following compounds were prepared without further
purification:
TABLE-US-00016 Cpd MS (MH.sup.+) 90 517 92 549 107 511 110 575 (M +
Na) 112 667 117 541 124 489 126 539 133 507 142 525
Example 30
{[3-({Methyl-[1-(naphthalene-2-carbonyl)-piperidin-4-yl]-amino}-methyl)-na-
phthalen-2-ylcarbamoyl]-naphthalen-1-yl-methyl}-phosphonic acid,
Cpd 102
[0256] Using the procedure of Example 29, substituting
(4-methylamino-piperidin-1-yl)-naphthalen-2-yl-methanone for
cyclohexylamine, Compound 102 was prepared: HPLC: 3.12 min; MS (ES)
m/z 672 (MH.sup.+).
Example 31
({3-[(1-Benzoyl-piperidin-4-ylamino)-methyl]-naphthalen-2-ylcarbamoyl}-nap-
hthalen-1-yl-methyl)-phosphonic acid, Cpd 44
[0257] Using the procedure of Example 29, substituting
(4-amino-piperidin-1-yl)-phenyl-methanone for cyclohexylamine,
Compound 44 was prepared: HPLC: 2.84 min; MS (ES) m/z 608
(MH.sup.+).
Example 32
({3-[4-(6-Chloro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbon-
yl]-naphthalen-2-ylcarbamoyl}-naphthalen-1-yl-methyl)-phosphonic
acid, Cpd 60
[0258] Using the procedure of Example 17, Compound 17k was
converted to Compound 32a.
[0259] To a suspension of Compound 32a (9.02 g, 17.9 mmol) in
1,4-dioxane (200 mL) was added a mixture of LiOH.H.sub.2O (2.25 g,
53.6 mmol) in water (25 mL). The mixture was stirred for 4.5 h,
then concentrated under reduced pressure at rt. The residue was
partitioned between 1N HCl and EtOAc, and the aqueous portion was
extracted with EtOAc (5.times.). The combined organic extracts were
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated under reduced pressure at rt. The solid was suspended
in MeOH, collected, washed with MeOH, and dried under
N.sub.2/vacuum to yield 6.87 g of Compound 32b as a white powder:
HPLC: 3.99 min.
[0260] A mixture of Compound 32b (2.85 g, 9.79 mmol) and excess
thionyl chloride was stirred until the solution became clear. The
solution was concentrated under reduced pressure at rt, and the
residue was taken up in hexanes and concentrated under reduced
pressure at rt. The residue was stirred with CH.sub.3CN, and the
solid was collected and dried under N.sub.2/vacuum to yield 2.45 g
of Compound 32c: HPLC: 4.10 min, 87%.
[0261] A mixture of Compound 32c (0.31 g, 0.66 mmol) Compound 32d
(0.33 g, 1.311 mmol; J. Med. Chem. 1987, 30(5), 814-819) in
CH.sub.3CN (15 mL) was refluxed for 1 h. The mixture was cooled to
rt, filtered, and concentrated under reduced pressure at rt. The
residue was purified by flash column chromatography (silica, 0-3%
MeOH/CH.sub.2Cl.sub.2) to yield 0.38 g of Compound 32e: HPLC: 3.98
min.
[0262] Compound 32e (0.18 g, 0.25 mmol) was deethylated by
Procedure A to yield Compound 60 (0.14 g): HPLC: 3.65 min; MS (ES)
m/z 669 (MH.sup.+).
##STR00117## ##STR00118##
[0263] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 32,
the following compounds were prepared without further
purification:
TABLE-US-00017 Cpd MS (MH.sup.+) 54 593 73 566 83 618 87 565 91 517
93 635 100 620 101 579 103 629 104 649 111 539 113 636 115 613 131
565
Example 33
({3-[Methyl-(4-phenyl-cyclohex-3-enyl)-carbamoyl]-naphthalen-2-ylcarbamoyl-
}-naphthalen-1-yl-methyl)-phosphonic acid, Cpd 46
[0264] To a stirred solution of Compound 33a (0.68 g, 3.96 mmol;
Syn. Comm. 1994, 24(6), 799-808) and a 2 mL of a 2M solution of
methyl amine in THF (6 mL) was added sodium triacetoxyborohydride
(1.30 g, 5.94 mmol) followed by glacial acetic acid (0.24 g, 3.96
mmol). After stirring for 2.5 h, the mixture was treated with water
and extracted with CH.sub.2Cl.sub.2 (3.times.). The combined
organic extracts were dried (Na.sub.2SO.sub.4), filtered (Celite)
and concentrated under reduced pressure at rt. The residue was
purified by flash column chromatography (silica, 0-10%
MeOH/CH.sub.2Cl.sub.2) to yield 0.25 g of Compound 33b as a light
brown tacky solid: HPLC: 1.91 min; MS (ES) m/z 188 (MH.sup.+).
[0265] Using the procedure described in Example 32, Compound 33b
was converted to Compound 46: HPLC: 3.97 min; MS (ES) m/z 605
(MH.sup.+).
##STR00119##
Example 34
[(3-Benzylcarbamoyl-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phos-
phonic acid, Cpd 119
[0266] Compound 119 was prepared from Compound 32b via a standard
BOP-Cl/TEA coupling and deethylation by Procedure A: HPLC: 3.81
min, 90%; MS (ES) m/z 525 (MH.sup.+).
Example 35
[(5-Bromo-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosph-
onic acid, Cpd 23
[0267] Compound 35a (6-bromobenzothiophene) was prepared by the
method described in J. Med. Chem. 1998, 41, 4486-4491. Compound 35a
(3.45 g, 16.2 mmol) was converted to 3.68 g of crude Compound 35b
by the method described in the reference cited supra: HPLC: 4.14
min, 53%.
[0268] Following the procedure of Example 1 for the conversion of
Compound 1c to Compound 9, Compound 35b was converted to Compound
23: HPLC: 4.53 min; MS (ES) m/z 475 (MH.sup.-).
##STR00120##
[0269] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 35,
the following compounds were prepared without further
purification:
TABLE-US-00018 Cpd MS (MH.sup.+) 5 412 10 None (verified by NMR) 29
396 (MH-) 76 474 (MH-) 99 476/478
Example 36
[(5-phenyl-benzo[b]thiophen-3-yl)-(naphthalen-2-ylcarbamoyl)-methyl]-phosp-
honic acid, Cpd 71
[0270] To a heat-gun dried flask under Ar was sequentially added
toluene (15 mL), Compound 35a (0.33 g, 0.91 mmol) and then tetrakis
triphenylphosphine Pd(0) (0.053 g, 0.046 mmol). After stirring for
30 min, the mixture was treated with a solution of phenyl boronic
acid, Compound 36a (0.17 g, 1.36 mmol) in EtOH (5 mL) followed by
saturated NaHCO.sub.3 (aq) (7.5 mL). After 4 h at reflux, the
mixture was cooled to rt and treated with brine (15 mL). The layers
were separated, and the aqueous portion was extracted with EtOAc
(3.times.) and the combined organic extracts were washed
sequentially with 0.1 N NaOH (aq) (3.times.), brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated under reduced
pressure at rt. The residue was purified by flash column
chromatography (silica, 0-3% MeOH/CH.sub.2Cl.sub.2) to yield 0.27 g
of Compound 36b: HPLC: 3.91 min, 95%; MS (ES) m/z 361
(MH.sup.+).
[0271] Following the procedure of Example 35 for the conversion of
Compound 35a to Compound 35b, Compound 36b was converted to
Compound 36c.
[0272] Following the procedure of Example 1 with Procedure A for
the conversion of Compound 1c to Compound 9, Compound 36c was
converted to Compound 71: HPLC: 4.84 min; MS (ES) m/z 572
(MH.sup.-).
##STR00121##
[0273] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 36,
the following compounds were prepared without further
purification:
TABLE-US-00019 Cpd MS (MH.sup.+) 143 623 (M + pyr)H.sup.+
Example 37
[(Naphthalen-2-ylcarbamoyl)-(1-phenyl-1H-indol-3-yl)-methyl]-phosphonic
acid, Cpd 82
[0274] N-phenyl indole Compound 37a was prepared by the procedure
described in JOC 2001, 66(23), 7729-7737.
[0275] Using the procedure described in Example 18, substituting
Compound 37a for Compound 18b, Compound 82 was prepared: HPLC: 4.04
min; MS (ES) m/z 457 (MH.sup.+).
##STR00122##
Example 38
[(3-Benzyloxy-naphthalen-2-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic
acid, Cpd 122
[0276] Using the procedure described in Example 17, substituting
Compound 38a (0.30 g, 1.89 mmol) for Compound 17i, Compound 38b
(0.38 g) was prepared: HPLC: 3.85 min, 95%; MS (ES) m/z 464
(MH.sup.+).
[0277] Using the method described in JACS 1998, 110(14), 4789,
Compound 38b (0.22 g, 0.48 mmol) was converted to Compound 38c
(0.16 g): HPLC: 4.43 min, 98%.
[0278] Compound 38c (0.14 g, 0.25 mmol) was deethylated by
Procedure A to give Compound 122 (0.114 g): HPLC: 4.08 min; MS (ES)
m/z 498 (MH.sup.+).
##STR00123##
[0279] Other compounds of the present invention may be prepared by
those skilled in the art by, varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 38,
the following compounds were prepared without further
purification:
TABLE-US-00020 Cpd MS (MH.sup.+) 108 408 121 524 123 480
Example 39
[Naphthalen-1-yl-(3-phenylcarbamoyloxy-naphthalen-2-yl-carbamoyl)-methyl]--
phosphonic acid, Cpd 95
[0280] Using the procedure described in Example 27, substituting
Compound 38b (0.19 g, 0.41 mmol) for Compound 27a and
phenylisocyanate for benzylisocyanate, Compound 39a (0.18 g) was
prepared: HPLC: 4.30 min, 95%; MS (ES) m/z 583 (MH.sup.+).
[0281] Compound 39a (0.18 g, 0.31 mmol) was deethylated by
Procedure A to give Compound 95 (0.12 g): HPLC: 4.16 min; MS (ES)
m/z 527 (MH.sup.+).
##STR00124##
Example 40
[(3-{[1-(Naphthalene-2-carbonyl)piperidine-4-carbonyl]-amino}-naphthalen-2-
-ylcarbamoyl)-naphthalen-1-yl-methyl]-phosphonic acid, Cpd 141
[0282] Compound 40a was synthesized by the method described in JACS
1993, 115(4), 1321-1329.
[0283] Using the procedure described in Example 17, substituting
Compound 40a (0.80 g, 3.11 mmol) for Compound 17c, Compound 40b
(0.53 g) was prepared: HPLC: 4.20 min.
[0284] Compound 40b (0.28 g, 0.50 mmol) was dissolved in TFA (1 mL)
and allowed to stand for 30 min. The solution was concentrated
under reduced pressure at rt to yield 0.47 g of Compound 40c as a
4.2 TFA solvate: HPLC: 3.40 min; MS (ES) m/z 463 (MH.sup.+).
[0285] To a solution of Compound 40c (0.47 g), diisopropylamine
(0.37 mL, 2.1 mmol), HOBt (0.068 g, 0.50 mmol), and
Boc-isonipecotic acid (0.115 g, 0.50 mmol) in CH.sub.2Cl.sub.2 (5
mL) was added DCC (0.103 g, 0.50 mmol). After stirring for 72 h,
the mixture was diluted with CH.sub.2Cl.sub.2 and filtered. The
filtrate was washed sequentially with 1N KHSO.sub.4, saturated
NaHCO.sub.3 (aq), and brine, then dried (Na.sub.2SO.sub.4),
filtered and concentrated under reduced pressure at rt. The residue
was crystallized from CH.sub.3CN to yield 0.14 g of Compound 40d as
a white solid: HPLC: 4.08 min; MS (ES) m/z 674 (MH.sup.+).
[0286] Compound 40d (0.14 g, 0.21 mmol) was stirred with TFA (1 mL)
for 45 min, then concentrated. The residue was dissolved in
CH.sub.2Cl.sub.2 (5 mL) containing DIPEA (0.21 mL, 1.2 mmol). To
the mixture was added 2-naphthoyl chloride (0.04 g, 0.21 mmol) and
the reaction stirred for 20 min. The mixture was washed
sequentially with 1N KHSO.sub.4 (aq), saturated NaHCO.sub.3 (aq),
and brine, then dried (Na.sub.2SO.sub.4), filtered and concentrated
under reduced pressure at rt to yield 0.15 g of Compound 40e as a
white solid: HPLC: 4.01 min.
[0287] Compound 40e was deethylated by Procedure A to yield
Compound 141: HPLC: 3.75 min; MS (ES) m/z 672 (MH.sup.+).
##STR00125##
[0288] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 40,
the following compounds were prepared without further
purification:
TABLE-US-00021 Cpd MS (MH.sup.+) 132 407
Example 41
[2-(2-Naphthalen-1-yl-2-phosphono-acetylamino)-naphthalen-1-yloxy]-acetic
acid methyl ester, Cpd 134
[0289] Using the procedure described in Example 38 for the
conversion of Compound 38a to 38c, substituting methyl bromoacetate
for benzyl bromide, Compound 41a was reacted to give Compound
41b.
[0290] Compound 41b was deethylated by Procedure A to yield
Compound 134: HPLC: 4.23 min; MS (ES) m/z 498 (MH.sup.+).
##STR00126##
Example 42
(Naphthalen-1-yl-{1-[2-oxo-2-(4-phenyl-piperidin-1-yl)-ethoxy]-naphthalen--
2-ylcarbamoyl}-methyl)-phosphonic acid, Cpd 114
[0291] Using the procedure of Example 32 for the saponification of
Compound 32a to 32b, Compound 41b (1.01 g, 1.89 mmol) was converted
to Compound 42a (1.12 g): HPLC: 3.78 min; MS (ES) m/z 522
(MH.sup.+).
[0292] Using the procedure described in Example 24, substituting
Compound 42a (0.25 g, 0.48 mmol) for Compound 24e, Compound 42b
(0.27 g) was prepared: HPLC: 4.54 min, 97%; MS (ES) m/z 665
(MH.sup.+).
[0293] Compound 42b (0.15 g, 0.23 mmol) was deethylated by
Procedure A to give of Compound 114 (0.096 g): HPLC: 4.19 min; MS
(ES) m/z 609 (MH.sup.+).
##STR00127##
[0294] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 40,
the following compounds were prepared without further
purification:
TABLE-US-00022 Cpd MS (MH.sup.+) 130 583
Example 43
{[(5-Chloro-benzo[b]thiophen-3-yl)-[2-(4-hydroxyl-phenyl)-vinylcarbamoyl]--
methyl}-methyl-phosphonic acid, Cpd 66
[0295] Compound 43a (0.100 g, 0.192 mmol), prepared as in Example
11, was deethylated by Procedure A and the crude product was
dissolved in 5 mL of methanol and treated with 0.210 g of KOH. The
mixture was stirred for 7.5 h, then acidified with 1N HCl (aq),
concentrated under reduced pressure at rt and purified by reverse
phase HPLC (12-90% MeCN/H.sub.2O) to yield 0.014 g of Compound 66
as a grey powder: HPLC: 3.04 min; 77%; MS (ES) m/z 422
(MH.sup.-).
##STR00128##
Example 44
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(2-hydroxy-phenyl)-vinylcarbamoyl]-me-
thyl}-methyl-phosphinic acid, Cpd 149
[0296] A solution of Compound 44a (0.29 g, 0.63 mmol; prepared
according to Example 6) in 15 mL of methanol containing 5 mL of 1N
NaOH (aq) was stirred for 25 min. The solution was concentrated
under reduced pressure, and the residue was suspended in 1N HCl
(aq) and stirred for 1 h. The solid was collected, rinsed
sequentially with 1N HCl and water, then dried under a stream of
N.sub.2 to yield 0.23 g of Compound 149 as a pale yellow powder:
HPLC: 3.71 min; MS (ES) m/z 422 (MH.sup.+).
##STR00129##
Example 45
[[2-(2-Amino-phenyl)-vinylcarbamoyl]-(5-chloro-benzo[b]thiophen-3-yl)-meth-
yl]-methyl-phosphinic acid, Cpd 151
[0297] Compound 45a (prepared according to Example 6) was converted
to compound 45b by the method of Example 10. Compound 45b was
deethylated according to Procedure A and purified by trituration
with 1N HCl (aq) to yield Compound 151: HPLC: 2.78 min; MS (ES) m/z
421 (MH.sup.+).
##STR00130##
[0298] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 45,
the following compounds were prepared without further
purification:
TABLE-US-00023 Cpd MS (MH.sup.+) 172 421
Example 46
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(2-ureido-phenyl)-vinylcarbamoyl]-met-
hyl}-methyl-phosphinic acid, Cpd 158
[0299] To a suspension of Compound 45b (0.14 g, 0.31 mmol), acetic
acid (0.4 mL) and water (1.6 mL) was added a five-fold excess of
sodium cyanate. The reaction was stirred at 60.degree. C. for 1 h,
and the crude product was collected, washed with water, dried under
a stream of N.sub.2 and deethylated by Procedure A. The product was
subjected to reverse phase HPLC (25-90% MeCN/H.sub.2O) to yield
0.026 g of Compound 158 as a white powder: HPLC: 3.22 min; MS (ES)
m/z 464 (MH.sup.+), and 0.037 g of Compound 159 as a white powder:
HPLC: 3.46 min; MS (ES) m/z 507 (MH.sup.+).
##STR00131##
Example 47
(Naphthalen-1-yl-styrylcarbamoyl-methyl)-phosphonic acid
didiethylcarbamoylmethyl ester, Cpd 180
[0300] To a solution of Compound 37 (0.21 g, 0.53 mmol) and
N,N-diethyl-2-hydroxyacetamide (0.15 g, 1.17 mmol) in pyridine (5
mL) was added 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole
(MSNT; 0.47 g, 1.59 mmol) and the mixture was stirred at rt for 3.5
h. The reaction was concentrated under reduced pressure, and the
residue taken up in EtOAc. The solution was washed sequentially
with 1N KHSO.sub.4 (aq), saturated NaHCO.sub.3 (aq), and brine,
then dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography (silica, 0-30% acetone/heptane) to yield 0.07 g of
Compound 180 as a yellow solid: HPLC: 3.88 min; MS (ES) m/z 594
(MH.sup.+).
##STR00132##
[0301] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 47,
the following compounds were prepared:
TABLE-US-00024 Cpd MS (MH.sup.+) 179 510 181 656
Example 48
2-Naphthalen-1-yl-2-(2-oxo-2,5-[1,3,2]dioxaphosphinan-2-yl)-N-styryl-aceta-
mide, Cpd 178
[0302] Using the procedure described in Example 47, Compound 37
(0.10 g, 0.27 mmol), 1,3-propanediol (0.02 g, 0.27 mmol), and MSNT
(0.48 g, 1.62 mmol) in pyridine (5 ml) afforded 0.01 g of Compound
178, as a white powder: HPLC: 3.52 min; MS (ES) m/z 408
(MH.sup.+).
[0303] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 48,
the following compound was prepared:
TABLE-US-00025 Cpd MS (MH.sup.+) 173 436
Example 49
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcrbamoyl]--
methyl}-methyl-phosphinic acid diethylcarbamoylmethyl ester, Cpd
185
[0304] Using the procedure described in Example 47, Compound 17
(0.25 g, 0.57 mmol), N,N-diethyl-2-hydroxyacetamide (0.37 g, 2.86
mmol), and MSNT (0.25 g, 0.86 mmol) in pyridine (5 ml) yielded 0.14
g of Compound 185, as a white powder (.about.3:1 mixture of
diastereomers). HPLC: 4.03 min (24%), 4.11 min (76%); MS (ES) m/z
555 (MH.sup.+).
[0305] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 49,
the following compound was prepared:
TABLE-US-00026 Cpd MS (MH.sup.+) Diastereomer ratio 183 513 1:1
Example 50
{(5-Chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl]-
-methyl}-methyl-phosphinic acid 2-amino-ethyl ester, Cpd 184
[0306] Using the procedure described in Example 47, Compound 17
(0.27 g, 0.61 mmol), N-Boc-ethanolamine (0.11 g, 0.67 mmol), and
MSNT (0.54 g, 1.83 mmol) in pyridine (5 mL) yielded 0.27 g of
Compound 50a, as a white powder: (.about.2:1 mixture of
diastereomers). HPLC: 4.17 min (22%), 4.20 min (46%); MS (ES) m/z
585 (MH.sup.+).
[0307] A solution of Compound 50a (0.27 g, 0.46 mmol) in 3 mL of
TFA was stirred for 30 min, then concentrated under reduced
pressure. The residue was purified by reverse phase HPLC (30-90%
MeCN/H.sub.2O) to afford 0.12 g of Compound 184 as a white powder
(TFA salt; .about.1:1 mixture of diastereomers by .sup.1H NMR);
HPLC: 3.17 min; MS (ES) m/z 485 (MH.sup.+).
##STR00133##
Example 51
2,2-Dimethyl-propionic acid
{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl-
]-methyl}-(2,2-dimethyl-propionyloxymethoxy)-phosphinoyloxymethyl
ester, Cpd 186 and
2,2-Dimethyl-propionic acid
{(5-chloro-benzo[b]thiophen-3-yl)-[2-(3,4-difluoro-phenyl)-vinylcarbamoyl-
]-methyl}-hydroxy-phosphinoyloxymethyl ester, Cpd 187
[0308] A solution of Compound 2 (0.25 g, 0.56 mmol), triethylamine
(0.31 mL, 2.24 mmol), and chloromethylpivaloate (0.32 ml, 2.24 g)
in DMF (2 ml) was heated at 60.degree. C. for 2.5 h. The mixture
was cooled to rt and concentrated under reduced pressure. The crude
product mixture was subjected to reverse phase HPLC (37.5-90%
MeCN/H.sub.2O) to yield 0.035 g of Compound 186 as a white powder;
HPLC: 4.77 min; MS (ES) m/z 672 (MH.sup.+), and 0.16 g of Compound
187 which was converted to its tromethamine salt by treatment of a
methanol solution of Compound 186 with 1 eq of
tris-(hydroxymethyl)methylamine. The mixture was concentrated under
reduced pressure to afford the tromethamine salt of Compound 187 as
a white powder: HPLC: 5.13 min; MS (ES) m/z 558 (MH.sup.+).
##STR00134##
[0309] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the procedure of Example 51,
the following compounds were prepared:
TABLE-US-00027 Cpd MS (MH.sup.+) 188 670 190 514 (MH.sup.-) 191
670
[0310] Using the procedure of Example 51, and substituting Compound
37 for Compound 2, the following compounds were prepared:
TABLE-US-00028 Cpd MS (MH.sup.+) 174 438 (MH.sup.-) 175 512 176 466
(MH.sup.-) 177 482
[0311] Using the procedure of Example 51, and substituting Compound
17 for Compound 2, the following compound was prepared:
TABLE-US-00029 Diastereomer Cpd MS (MH.sup.+) ratio 182 556 3:2
[0312] The following compounds can be made by those skilled in the
art by using Example 6 followed by Example 51, and varying the
starting materials, reagent(s) and conditions used: compounds 210,
211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223,
224, 225, 226, 227, 316, 317, 318, 319, 320, 321, 322, and 323.
[0313] The following compounds can be made by those skilled in the
art by using Example 11 followed by Example 51, and varying the
starting materials, reagent(s) and conditions used: compounds 228,
229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,
242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254,
255, 256, 257, 258, 259, 260, 261, 262, 263, 282, 283, 284, 285,
286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298,
299, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335,
336, 337, 338, 339, 348, 349, 350, 351, 352, 353, 354, and 355.
Example 52
2-(5-Chloro-benzo[b]thiophen-3-yl)-N-[2-(3,4-difluoro-phenyl)-vinyl]-2-(2--
oxo-2.lamda..sup.5-[1,3,2]dioxaphosphinan-2-yl)-acetamide, Cpd
189
[0314] A solution of Compound 1a (1.75 g, 6.69 mmol) and Compound
52a (prepared according to JACS 1969, 91(24), 6838-6841; 1.36 g,
10.04 mmol) in toluene (15 mL) was refluxed for 24 h. After cooling
to rt, the mixture was concentrated under reduced pressure and the
residue was purified by flash column chromatography (silica; 0-30%
acetone/heptane) to afford 1.0 g of Compound 52b as a viscous oil:
HPLC: 3.03 min; MS (ES) m/z 303 (MH.sup.+).
[0315] From Compound 52b (0.51 g, 1.69 mmol) was prepared 0.28 g of
Compound 189 by the procedure of Example 1: HPLC: 3.96 min; MS (ES)
m/z 484 (MH.sup.+).
##STR00135##
[0316] The following compounds can be made by those skilled in the
art by using Example 52 and varying the starting materials,
reagent(s) and conditions used: compounds 264, 265, 266, 267, 268,
269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281,
340, 341, 342, 343, 344, 345, 346, and 347.
Biological Experimental Examples
[0317] The utility of the compounds of the present invention as a
serine protease inhibitor and, particularly, as a chymase inhibitor
useful for the treatment of inflammatory or serine protease
mediated disorders can be determined according to the procedures
described herein.
Example 1
Enzyme-Catalyzed Hydrolysis Assays
[0318] Enzyme-catalyzed hydrolysis rates were measured
spectro-photometrically using human skin chymase (Cortex Biochem),
a chromogenic substrate (Suc-Ala-Ala-Pro-Phe-pNa) (Bachem) in
aqueous buffer (450 mM Tris, 1800 mM NaCl, pH 8.0), and a
microplate reader (Molecular Devices). IC.sub.50 experiments were
conducted by fixing the enzyme and substrate concentrations (10 nM
enzyme, 0.7 mM substrate) and varying the inhibitor concentration.
Changes in absorbance at 405 nM were monitored using the software
program Softmax (Molecular Devices), upon addition of enzyme, with
and without inhibitor present at 37.degree. C. for 30 minutes.
Percent inhibition was calculated by comparing the initial reaction
slopes of the samples without inhibitor to those with inhibitor.
IC.sub.50 values were determined using a four parameter fit
logistics model. The term "NT" indicates a compound that was not
tested.
[0319] Table VI summarizes the assay results for chymase inhibition
for compounds of the present invention:
TABLE-US-00030 TABLE VI IC.sub.50 (.mu.M) Cpd Chymase N 1 0.010
.+-. 0 2 2 0.011 .+-. 0 2 3 0.013 .+-. 0.007 2 4 0.016 .+-. 0.005 2
5 0.019 .+-. 0.005 2 6 0.020 .+-. 0 2 7 0.021 .+-. 0.004 2 8 0.021
.+-. 0.010 4 9 0.029 .+-. 0.009 2 10 0.029 .+-. 0.010 3 11 0.037
.+-. 0.010 2 12 0.038 .+-. 0.013 6 13 0.040 .+-. 0.020 3 14 0.050
.+-. 0.010 2 15 0.052 .+-. 0.015 3 16 0.055 .+-. 0.005 2 17 0.058
.+-. 0.012 7 18 0.060 .+-. 0.020 3 19 0.066 .+-. 0.010 6 20 0.080
.+-. 0.004 2 21 0.080 .+-. 0.020 2 22 0.090 .+-. 0.028 4 23 0.100
.+-. 0.030 3 24 0.100 .+-. 0.033 3 25 0.109 .+-. 0.030 3 26 0.120
.+-. 0.030 4 27 0.130 .+-. 0.020 2 28 0.160 .+-. 0.004 2 29 0.166
.+-. 0.012 2 30 0.170 .+-. 0.010 2 31 0.190 1 32 0.210 .+-. 0.010 2
33 0.210 .+-. 0.690 2 34 0.220 .+-. 0.010 2 35 0.235 .+-. 0.045 2
36 0.240 .+-. 0.010 2 37 0.250 .+-. 0.120 7 38 0.284 .+-. 0.108 2
39 0.310 .+-. 0.040 2 40 0.320 .+-. 0.140 2 41 0.330 .+-. 0.020 2
42 0.340 .+-. 0.130 4 43 0.350 .+-. 0.070 2 44 0.350 .+-. 0.220 2
45 0.371 .+-. 0.110 2 46 0.388 .+-. 0.116 2 47 0.410 .+-. 0.100 2
48 0.421 .+-. 0.151 2 49 0.430 .+-. 0.090 2 50 0.430 .+-. 0.150 4
51 0.460 .+-. 0.060 2 52 0.480 .+-. 0.180 2 53 0.490 .+-. 0.160 2
54 0.510 .+-. 0.124 3 55 0.520 .+-. 0.510 2 56 0.606 .+-. 0.130 2
57 0.609 1 58 0.630 .+-. 0.130 4 59 0.635 1 60 0.663 1 61 0.710 1
62 0.820 .+-. 0.500 3 63 0.830 .+-. 0.180 4 64 0.830 .+-. 0.080 2
65 0.840 .+-. 0.190 3 66 0.868 .+-. 0.130 6 67 0.920 .+-. 0.250 4
68 0.920 .+-. 0.530 2 69 0.930 .+-. .0950 2 70 0.930 .+-. 0.070 2
71 1.000 .+-. 0.300 5 72 1.300 .+-. 0.610 2 73 1.352 .+-. 0.168 3
74 1.390 .+-. 0.554 2 75 1.400 .+-. 0.600 3 76 1.430 .+-. 0.451 2
77 1.480 .+-. 0.450 2 78 1.500 .+-. 0.430 2 79 1.600 1 80 1.650
.+-. 0.680 2 81 1.700 .+-. 0.210 6 82 1.700 .+-. 0.410 2 83 1.723 1
84 1.750 .+-. 0.285 2 85 1.800 .+-. 1.200 2 86 1.900 .+-. 0.400 2
87 2.036 1 88 2.040 .+-. 0.190 3 89 2.100 .+-. 0.200 2 90 2.153 1
91 2.320 1 92 2.400 1 93 2.703 1 94 2.755 1 95 2.800 1 96 2.800 1
97 2.882 .+-. 0.899 2 98 2.900 1 99 2.963 .+-. 1.180 2 100 3.001
.+-. 1.431 3 101 3.115 1 102 3.450 1 103 3.627 1 104 3.879 .+-.
2.414 3 105 4.100 1 106 4.300 1 107 4.300 .+-. 0.030 2 108 4.338 1
109 4.400 1 110 4.451 1 111 4.617 1 112 4.735 .+-. 1.655 5 113
4.803 .+-. 1.688 2 114 4.899 .+-. 1.339 2 115 5.362 1 116 5.400 1
117 5.624 .+-. 1.074 2 118 5.720 .+-. 0.013 2 119 5.800 1 120 5.860
.+-. 1.080 5 121 5.900 1 122 5.944 .+-. 1.688 2 123 6.600 1 124
6.700 1 125 6.700 1 126 7.000 1 127 7.000 .+-. 1.100 2 128 7.300 1
129 7.400 1 130 7.436 .+-. 3.734 2 131 7.681 1 132 7.900 1 133
8.083 .+-. 3.153 4 134 8.110 .+-. 4.753 2 135 8.300 1 136 8.630
.+-. 0.810 2 137 8.665 1 138 8.700 1 139 8.800 1 140 9.200 .+-.
0.730 6 141 9.500 1 142 9.538 .+-. 4.204 2 143 9.800 1 144 1.26
.+-. 0.29 2 145 0.035 .+-. 0.02 2 146 0.11 .+-. 0 2 147 1.44 .+-.
0.48 2 148 0.23 .+-. 0.04 2 149 0.043 .+-. 0 2 150 0.091 .+-. 0.02
2 151 0.40 .+-. 0.12 2 152 0.13 .+-. 0.03 2 153 0.06 .+-. 0.01 2
154 0.036 .+-. 0.05 2 155 0.34 .+-. 0.04 2 156 0.036 .+-. 0.01 2
157 11.0 .+-. 1.2 2 158 6.0 .+-. 1.9 2 159 3.0 .+-. 0.19 2 160
0.065 .+-. 0.02 2 161 0.0035 .+-. 0 2 162 0.0090 .+-. 0 2 163 0.017
.+-. 0 2 164 0.10 .+-. 0.02 2 165 0.078 .+-. 0.03 2 166 0.0387 .+-.
0.02 2 167 0.017 .+-. 0.04 2 168 0.0059 .+-. 0.01 2 169 0.042 .+-.
0 2 170 0.0031 .+-. 0 2 171 0.025 .+-. 0.01 2 172 0.041 .+-. 0.02 2
199 0.0018 .+-. 0 2
Example 2
Anti-Asthmatic Effects in a Sheep Model of Asthma
[0320] The efficacy of Compound 17 for the treatment of asthma was
evaluated in a validated model of Ascaris suum antigen-induced
asthmatic response in conscious sheep (Abraham, W. M., Pharmacology
of allergen-induced early and late airway responses and
antigen-induced airway hyperresponsiveness in allergic sheep,
Pulmonary Pharmacology, 1989, 2, 33-40).
Experimental Protocol
[0321] Baseline (BSL) dose response curves to aerosol carbachol
were obtained from historical control responses prior to antigen
challenge. Baseline values of specific lung resistance (SR.sub.L)
were obtained and the sheep were then given a specified amount (mg)
of the test compound as an inhaled aerosol or as a oral dose at a
specified time before antigen challenge. Post-drug measurements of
SR.sub.L were obtained and the sheep were then challenged with
Ascaris suum antigen. Measurements of SR.sub.L were obtained
immediately after challenge, hourly from 1-6 h after challenge and
on the half-hour from 61/2-8 h after challenge. Measurements of
SR.sub.L were obtained 24 h after challenge followed by a 24 h
post-challenge with carbachol to measure airway
hyperreactivity.
[0322] Compound 17 was administered as an aerosol at 4.5 mg/dose
(ca. 0.1 mg/Kg/dose, based on a 45 Kg sheep), twice-a-day (BID) for
three consecutive days, followed by a dose on day 4, 0.5 h prior to
antigen challenge. Ascaris suum antigen challenge was given at the
zero time point.
[0323] Compound 17 was administered as an oral solution at 15
mg/Kg/dose, twice-a-day (BID) for three consecutive days, followed
by a dose on day 4, 2 h prior to antigen challenge. Ascaris suum
antigen challenge was given at the zero time point.
[0324] FIG. 1 shows that after aerosol administration the early
airway response (0-2 h after antigen challenge) was unchanged and
that the late airway response (6-8 h after antigen challenge) was
completely blocked (n=2 sheep/group).
[0325] FIG. 2 shows that the delayed airway hyperreactivity
measured at 24 h post antigen challenge as measured using carbachol
challenge was also completely blocked by compound following aerosol
administration.
[0326] FIG. 3 shows that after oral administration the early airway
response (0-2 h after antigen challenge) was unchanged and that the
late airway response (6-8 h after antigen challenge) was completely
blocked (n=2 sheep/group).
[0327] FIG. 4 shows that the delayed airway hyperreactivity
measured at 24 h post antigen challenge as measured using carbachol
challenge was also completely blocked by compound following oral
administration.
Example 3
Pharmacokinetic Assay for Evaluation of Oral Absorption Potential
Procedural Overview
[0328] Male Sprague Dawley rats, weighing 250-300 g, were fasted
overnight then dosed by oral gavage at a level of 15 mg/kg with a
compound. Compounds were formulated in 20% hydroxy-beta-cyclo
dextran.
[0329] Blood samples (0.5 mL) were collected into lithium
heparinized tubes at 0.5, 1.0 and 2.0 h post dose via orbital sinus
puncture. Blood samples were centrifuged at 2000 rpm for .about.3
min for cell removal, approximately 200 .mu.L of plasma supernatant
was then transferred to a clean vial, frozen then placed on dry ice
and delivered to SFBC Analytical Labs, Inc. for analysis.
[0330] Plasma samples were prepared as follows. Two hundred
microliters of acetonitrile containing 1 .mu.M internal standard
was added to 100 .mu.L of plasma to precipitate proteins. Samples
were centrifuged at 5000 g for 5 min and supernatant removed for
analysis by LC-MS. Two hundred microliters of water was added to
adjust sample solvent strength and prevent peak splitting.
Calibration standards were prepared by adding appropriate volumes
of stock solution directly into plasma and treated identically to
collected plasma samples. Calibration standards were prepared in
the range of 0.1 to 10 .mu.M for quantitation. LC-MS analysis was
performed using MRM (Multiple Reaction Monitoring) detection of
characteristic ions for each drug candidate and internal
standard.
TABLE-US-00031 PK Data (N = 2) C.sub.Max (.mu.M) Cpd @ 2 h 173 0.1
.+-. 0.02 174 0.56 .+-. 0.36 175 0.2 .+-. 0.03 176 0.3 .+-. 0.04
177 2.0 .+-. 1.1 178 4.1 .+-. 0.28 179 <0.1 .+-. 0.0 180 <0.1
.+-. 0.0 181 0.2 .+-. 0.05 (C.sub.max at 30 min) 182 11.8 .+-. 3.26
183 0.1 .+-. 0.01 184 0.1 .+-. 0.05 185 2.1 .+-. 0.23 186 20.1 .+-.
3.5 187 21.4 .+-. 11 188 0.1 .+-. 0.05 189 21.1 .+-. 2.3 190 2.3
.+-. 0.55 191 19 (N = 1)
[0331] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *