U.S. patent application number 11/714031 was filed with the patent office on 2007-11-01 for aryl and heteroaryl compounds, compositions, and methods of use.
Invention is credited to Devi Reddy Gohimmukkula, Adnan M.M. Mjalli, Sameer Tyagi.
Application Number | 20070254916 11/714031 |
Document ID | / |
Family ID | 36539849 |
Filed Date | 2007-11-01 |
United States Patent
Application |
20070254916 |
Kind Code |
A1 |
Mjalli; Adnan M.M. ; et
al. |
November 1, 2007 |
Aryl and heteroaryl compounds, compositions, and methods of use
Abstract
This invention provides aryl and heteroaryl compounds, methods
of their preparation, pharmaceutical compositions comprising the
compounds, and their use in treating human or animal disorders. The
compounds of the invention may be useful as antagonists, or partial
antagonist of factor IX and/or factor XI and thus, may be used to
inhibit the intrinsic pathway of blood coagulation. The compounds
may be useful in a variety of applications including the
management, treatment and/or control of diseases caused in part by
the intrinsic clotting pathway utilizing factor IX and/or XI.
Inventors: |
Mjalli; Adnan M.M.; (Oak
Ridge, NC) ; Gohimmukkula; Devi Reddy; (Jamestown,
NC) ; Tyagi; Sameer; (High Point, NC) |
Correspondence
Address: |
KILPATRICK STOCKTON LLP - 41305;CHARLES CALKINS
1001 WEST FOURTH STREET
WINSTON-SALEM
NC
27101
US
|
Family ID: |
36539849 |
Appl. No.: |
11/714031 |
Filed: |
March 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11069521 |
Mar 1, 2005 |
7208601 |
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11714031 |
Mar 5, 2007 |
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10913168 |
Aug 6, 2004 |
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11069521 |
Mar 1, 2005 |
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60493879 |
Aug 8, 2003 |
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60493878 |
Aug 8, 2003 |
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60493903 |
Aug 8, 2003 |
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Current U.S.
Class: |
514/311 ;
514/314 |
Current CPC
Class: |
C07D 409/12 20130101;
A61P 9/10 20180101; C07D 405/12 20130101; A61P 9/00 20180101; A61P
7/02 20180101; C07D 405/04 20130101; A61P 43/00 20180101; A61P
13/12 20180101; A61P 3/00 20180101; A61P 7/08 20180101; A61K 31/47
20130101; C07D 217/26 20130101; A61P 9/06 20180101; A61P 15/06
20180101; A61P 37/02 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/311 ;
514/314 |
International
Class: |
A61K 31/47 20060101
A61K031/47; A61P 9/00 20060101 A61P009/00 |
Claims
1. A pharmaceutical composition comprising the compound of Formula
(X) ##STR119## wherein R.sub.101 is selected from the group
consisting of --H, or --CH.sub.2-thienyl wherein the thienyl group
in --CH.sub.2-thienyl is optionally substituted with --Br or
--CH.sub.3; R.sub.102 is selected from the group consisting of
--C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of --H, --CH.sub.3, --CF.sub.3, --Cl, --Br, --F, --C(O)CH.sub.3,
--CH.sub.2CH.sub.3, --CH.dbd.CH.sub.2, --CH.sub.2OH,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.3, ##STR120##
R.sub.104 is selected from the group consisting of ##STR121## and Y
is selected from the group consisting of H, ##STR122## or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
2. The pharmaceutical composition according to claim 1, wherein
R.sub.104 is ##STR123##
3. The pharmaceutical composition according to claim 1, wherein
R.sub.103 is optionally substituted --CH.sub.2-2-yl-thienyl or
optionally substituted --CH.sub.2-phenyl.
4. The pharmaceutical composition according to claim 1, wherein
R.sub.103 is optionally substituted --CH.sub.2-2-yl-thienyl.
5. The pharmaceutical composition according to claim 4, wherein
R.sub.101 is H.
6. The pharmaceutical composition according to claim 1, wherein Y
is selected from the group consisting of ##STR124##
7. The pharmaceutical composition according to claim 1, wherein Y
is -methylene-cyclopentyl.
8. The pharmaceutical composition according to claim 1, wherein the
pharmaceutical composition is prepared in a dose in a range of from
about 0.01 to 1,000 mg/kg of body weight per day.
9. The pharmaceutical composition of claim 1, wherein the compound
of Formula (X) is an antagonist of factor XI or factor IX/XI
activity.
10. The pharmaceutical composition of claim 9, wherein the compound
of Formula (X) is a partial antagonist of both factor XI and factor
XI/IX activity, wherein a partial antagonist comprises a compound
that inhibits less than complete activity at a physiological
dose.
11. The pharmaceutical composition of claim 9, comprising a
therapeutically effective amount of the compound of Formula (X),
wherein said therapeutically effective amount of Formula (X)
preferentially inhibits the intrinsic clotting cascade as compared
to the extrinsic clotting cascade.
12. The pharmaceutical composition of claim 11, wherein said
therapeutically effective amount of Formula (X) comprises an amount
sufficient to achieve and maintain a sustained blood level that at
least partially antagonizes factor XI or factor IX/XI biological
activity.
13. The pharmaceutical composition of claim 1, wherein the compound
of Formula (X) is an antagonist of factor IX activity.
14. The pharmaceutical composition of claim 13, wherein the
compound of Formula (X) is a partial antagonist of factor IX
activity, wherein a partial antagonist comprises a compound that
inhibits less than complete activity at a physiological dose.
15. The pharmaceutical composition of claim 1, comprising a
therapeutically effective amount of the compound of Formula (X),
wherein said therapeutically effective amount comprises a
sufficient amount of the compound of Formula (X) to at least
partially inhibit the biological activity of factor IX in a
subject.
16. The pharmaceutical composition of claim 1, comprising a
therapeutically effective amount of the compound of Formula (X),
wherein said therapeutically effective amount comprises a
sufficient amount of the compound of Formula (X) to at least
partially inhibit the biological activity of factor IX in a
subject.
17. The pharmaceutical composition of claim 16, wherein said
therapeutically effective amount of Formula (X) preferentially
inhibits the intrinsic clotting cascade as compared to the
extrinsic clotting cascade.
18. The pharmaceutical composition of claim 1, wherein said
therapeutically effective amount of Formula (X) comprises a
sufficient amount of the compound of Formula (X) for at least
partial amelioration of at least one factor IX-mediated
disease.
19. The pharmaceutical composition of claim 1 in the form of an
oral dosage or parenteral dosage unit.
20. A method comprising administering to a subject a compound of
Formula (X) ##STR125## wherein R.sub.101 is selected from the group
consisting of --H, or --CH.sub.2-thienyl wherein the thienyl group
in --CH.sub.2-thienyl is optionally substituted with --Br or
--CH.sub.3; R.sub.102 is selected from the group consisting of
--C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of ##STR126## R.sub.104 is selected from the group consisting of
##STR127## and Y is selected from the group consisting of H,
##STR128## or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
21. The method according to claim 20, wherein the compound of
Formula (X) is delivered as a part of a pharmaceutical composition
comprising a therapeutically effective amount of said compound of
Formula (X) and one or more pharmaceutically acceptable carriers,
excipients, or diluents.
22. The method according to claim 20, wherein R.sub.104 is
##STR129##
23. The method according to claim 22, wherein R.sub.101 is --H.
24. The method according to claim 20, wherein R.sub.103 is
optionally substituted --CH.sub.2-2-yl-thienyl or optionally
substituted --CH.sub.2-phenyl.
25. The method according to claim 20, wherein Y is selected from
the group consisting of ##STR130##
26. The method according to claim 20, wherein Y is
-methylene-cyclopentyl.
27. The method according to claim 20, wherein the compound of
Formula (X) is selected from the group consisting of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-phenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionic
acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid
methyl ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline--
3-carbonyl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic
acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid methyl
ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-furan-3-yl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-isopropyl-phenyl)-thiophen-2-yl]-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-vinyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-p-tolyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-chloro-phenyl)-thiophen-2-yl]-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-ethyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-furan-2-yl-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(2-trifluoromethyl-phenyl)-propionic acid,
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid tert-butyl ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(3,5-difluorophenyl)-propionic acid,
[[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(-
5-methyl-thiophen-2-ylmethyl)-amino]-acetic acid,
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester,
{(4-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid,
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid,
Benzo[b]thiophen-3-yl-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoq-
uinoline-3-carbonyl]-amino}-acetic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(4-fluoro-phenyl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(3,3-dimethyl-but-1-enyl)-thiophen-2-yl]-propionic
acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid methyl
ester,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-methyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid,
3-(5-Bromo-thiophen-2-yl)-2(R)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-chloro-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-chloro-furan-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(2,5-dichloro-thiophen-3-yl)-propionic acid,
(5-Bromo-thiophen-2-yl)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-is-
oquinoline-3-carbonyl]-amino}-acetic acid,
3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethy-
l-isoquinoline-3-carbonyl]-amino}-propionic acid,
3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-c-
yclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinol-
ine-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic
acid,
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinol-
ine-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic
acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-furan-2-yl)-propionic acid,
2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-c-
arbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isop-
ropyl-thiophen-2-yl)-propionic acid,
2(S)-{[1-Cyclopentylmethyl-7-(4-trans-ethyl-cyclohexyloxy)-isoquinoline-3-
-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3--
carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[6-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-phenyl)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
2(S)-{[7-(4-tert-Butyl-benzoyl)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
3-(5-Acetyl-thiophen-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylm-
ethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-(5-isopropyl-thiophen-2-ylmethyl)-2(R)-methanesulfonylamino-2-oxo-
-ethyl]-amide, and
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-(5-isopropyl-thiophen-2-ylmethyl)-2(S)-methanesulfonylamino-2-oxo-
-ethyl]-amide,
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-benzyloxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide,
and
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxyl-
ic acid
[1-hydroxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide.
28. The method according to claim 20, wherein said compound of
formula (X) inhibits up to 95% of factor IX activity.
29. A method of treating stroke, myocardial infarction, an
aneurysm, or thrombosis comprising the method of claim 20.
30. The method of claim 20, wherein the compound of Formula (X) is
an antagonist of factor IX activity.
31. The method of claim 20, wherein said compound of Formula (X) is
a partial antagonist of factor IX, wherein a partial antagonist
comprises a compound that inhibits less than complete activity at a
physiological dose.
32. The method of claim 20, wherein the compound of Formula (X)
antagonizes blood clotting mediated by factor IX.
33. The method of claim 20, wherein said compound of Formula (X) is
administered in an amount sufficient to partially antagonize the
biological activity of factor IX in said subject.
34. The method of claim 21, wherein said therapeutically effective
amount of the compound of Formula (X) comprises a sufficient amount
of the compound of Formula (X) to at least partially inhibit the
intrinsic clotting cascade in said subject.
35. The method of claim 21, wherein said therapeutically effective
amount of Formula (X) preferentially inhibits the intrinsic
clotting cascade as compared to the extrinsic clotting cascade.
36. The method of claim 21, wherein said therapeutically effective
amount of the compound of Formula (X) comprises a sufficient amount
of the compound of Formula (X) for treatment or prevention of
factor IX-mediated diseases.
37. The method of claim 20, wherein said pharmaceutical composition
is administered in the form of an oral dosage or parenteral dosage
unit.
38. The method of claim 20, wherein said compound of Formula (X) is
administered as a dose in a range from about 0.01 to 1,000 mg/kg of
body weight per day.
39. The method of claim 36, wherein said factor IX-mediated disease
comprises stroke.
40. The method of claim 36, wherein said factor IX-mediated disease
comprises deep vein thrombosis.
41. The method of claim 40, wherein said thrombosis is associated
with surgical procedures, long periods of confinement, acquired or
inherited pro-coagulant states including anti-phospholipid antibody
syndrome, protein C deficiency and protein S deficiency, or acute
and chronic inflammation including recurrent miscarriage or
Systemic Lupus Erythmatosis (SLE).
42. The method of claim 36, wherein said factor IX-mediated disease
comprises clotting associated with the treatment of kidney disease
by hemodialysis and/or venous hemofiltration.
43. The method of claim 36, wherein said factor IX-mediated disease
comprises cardiovascular disease.
44. The method of claim 43, wherein said cardiovascular disease
comprises myocardial infarction, arrhythmia, or aneurysm.
45. The method of claim 20, wherein said compound of Formula (X) is
used to replace or supplement compounds that reduce clotting.
46. The method of claim 21, wherein said pharmaceutical composition
further comprises one or more therapeutic agents.
47. A method for the inhibition of the normal biological function
of factor XI or factor IX/XI comprising the method of claim 20.
48. A method to inhibit blood clotting comprising the method of
claim 20.
Description
STATEMENT OF RELATED APPLICATIONS
[0001] This application claims priority as a divisional application
under 35 USC .sctn. 120 to U.S. application Ser. No. 11/069,521,
which was filed on Mar. 1, 2005, which claims priority as a
continuation in part application to U.S. application Ser. No.
10/913,168 filed on Aug. 6, 2004, which in turn claims priority
under 35 USC 119 to the following U.S. Provisional Patent
Applications: Ser. No. 60/493,879, filed Aug. 8, 2003, entitled
"Aryl and Heteroaryl Compounds as Antiviral agents"; Ser. No.
60/493,878, filed Aug. 8, 2003, entitled "Aryl and Heteroaryl
Compounds and Methods to Modulate Red Blood Cell Production"; Ser.
No. 60/493,903, filed Aug. 8, 2003, entitled "Aryl and Heteroaryl
Compounds and Methods to Modulate Coagulation", the entirety of all
are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to aryl and heteroaryl compounds and
compositions that may be antagonists of the intrinsic clotting
pathway by binding to and inhibiting the function of factor XI or
of both factors XI and IX, and methods of use for such compounds
and compositions.
BACKGROUND OF THE INVENTION
[0003] Hemostasis, the arrest of bleeding from an injured blood
vessel, requires the coordinated endeavors of vascular, platelet,
and plasma factors to eventually form a hemostatic seal or a blood
clot. In normal hemostasis, collective activity of these factors is
counterbalanced by regulatory mechanisms to limit the accumulation
of platelets and fibrin in the area of injury.
[0004] Upon injury to a blood vessel, vascular factors reduce blood
flow from the blood vessel by local vasoconstriction and
compression of injured vessels. At the same time, platelets adhere
to the site of vessel wall injury and form aggregates called
hemostatic plugs, which form the first key element of the
hemostatic seal. Platelets also release factors that provide
surface membrane sites and components for the formation of
enzyme/cofactor complexes in blood coagulation reactions. Through a
series of interacting and propagating zymogen activations, the
activated form of one plasma factor catalyzes the activation of the
next plasma factor. This cascade of blood coagulation reactions
eventually forms a fibrin clot. The fibrin clot, an insoluble
fibrin matrix that radiates from and anchors the hemostatic plug,
is the second key element of the hemostatic seal.
[0005] Specifically, the cascade of blood coagulation reactions
discussed involves two interdependent pathways, an intrinsic
pathway and an extrinsic pathway. Both pathways ultimately
catalyzes the proteolytic activation of factor X to factor Xa.
[0006] Damage to the blood vessel or a negatively charged surface
initiates blood clotting by the intrinsic pathway. As seen in FIG.
1, the major components of the intrinsic pathway include factor
VIII, a non-enzymatic co-factor, and factors IX and XI, zymogen
serine proteases. The initiation of the intrinsic pathway results
in the activation of factor XI to XIa. Factor XIa, as well as the
presence of the factor VIIa/tissue factor complex involved in the
extrinsic pathway, catalyzes the activation of factor IX to factor
Ixa. The presence of factor IXa, in combination with the activated
form of factor VIII on an appropriate phospholipid surface, results
in the formation of a tenase complex (10). The tenase complex
catalyzes the formation of factor Xa from its zymogen, factor
X.
[0007] Exposure of blood to injured tissue initiates blood clotting
by the extrinsic pathway. As is shown in FIG. 1, the major
components of the extrinsic pathway are factor VII, a zymogen
serine protease, and tissue factor, a membrane bound protein.
Tissue factor serves as the requisite non-enzymatic co-factor for
factor VII. The initiation of the extrinsic pathway is thought to
be an autocatalytic event resulting from the activation of factor
VII by trace levels of activated factor VII (factor VIIa), both of
which are bound to newly exposed tissue factor on membrane surfaces
at sites of vascular damage (20). The factor VIIa/tissue factor
complex directly catalyzes the formation of factor Xa from factor
X.
[0008] Once the initial intrinsic or extrinsic cascade results in
the activation of factor X, factor Xa catalyzes the penultimate
step in the blood coagulation cascade, the formation of serine
protease thrombin. As seen in FIG. 2, thrombin formation occurs
when a prothrombinase complex, comprising of factor Xa, the
non-enzymatic co-factor Va and the substrate prothrombin, is
assembled on an appropriate phospholipid surface (30). Once formed,
thrombin functions as part of a feedback loop, controlling the
activation of factors V and VIII. It additionally catalyzes both
the activation of factor VIII and the conversion of fibrinogen to
fibrin. Finally, the factor VIIIa interacts with fibrin to catalyze
the formation of a thrombus, or crosslinked fibrin clot.
[0009] In normal hemostasis, the process of clot formation (blood
coagulation) and clot dissolution (fibrinolysis) is delicately
balanced. A slight imbalance between the processes of clot
formation and dissolution can lead to excessive bleeding or
thrombosis. Many significant disease states are related to abnormal
hemostasis. With respect to the coronary arterial vasculature,
abnormal thrombus formation due to the rupture of an established
atherosclerotic plaque is the major cause of acute myocardial
infarction and unstable angina. Moreover, treatment of an occlusive
coronary thrombus by either thrombolytic therapy or percutaneous
transluminal coronary angioplasty (PTCA) is often accompanied by an
acute thrombotic reclosure of the affected vessel which requires
immediate resolution. With respect to the venous vasculature, a
high percentage of patients undergoing major surgery in the lower
extremities or the abdominal area suffer from thrombus formation in
the venous vasculature which can result in reduced blood flow to
the affected extremity and a predisposition to pulmonary embolism.
Disseminated intravascular coagulopathy commonly occurs within both
vascular systems during septic shock, certain viral infections and
cancer and is characterized by the rapid consumption of coagulation
factors and systemic coagulation which results in the formation of
life-threatening thrombi occurring throughout the vasculature
leading to widespread organ failure.
[0010] Pathogenic thrombosis in the arterial vasculature is a major
clinical concern in today's medicine. It is the leading cause of
acute myocardial infarction which is one of the leading causes of
death in the western world. Recurrent arterial thrombosis also
remains one of the leading causes of failure following enzymatic or
mechanical recanalization of occluded coronary vessels using
thrombolytic agents or percutaneous transluminal coronary
angioplasty (PTCA), respectively [Ross, A. M., Thrombosis in
Cardiovascular Disorder, p. 327, W.B. Saunders Co. (Fuster, V. and
Verstraete, M. edit. 1991); Califf, R. M. and Willerson, J. T., Id.
at p 389]. In contrast to thrombotic events in the venous
vasculature, arterial thrombosis is the result of a complex
interaction between fibrin formation resulting from the blood
coagulation cascade and cellular components, particularly
platelets, which make up a large percentage of arterial thrombi.
Heparin, the most widely used clinical anticoagulant administered
intravenously, has not been shown to be universally effective in
the treatment or prevention of acute arterial thrombosis or
rethrombosis [Prins, M. H. and Hirsh, J., J. Am. Coll. Cardiol.,
67: 3A (1991)].
[0011] Besides the unpredictable, recurrent thrombotic reocclusion
which commonly occurs following PTCA, a profound restenosis of the
recanalized vessel occurs in 30 to 40% of patients 1 to 6 months
following this procedure [Califf, R. M. et al., J. Am. Coll.
Cardiol., 17: 2B (1991)]. These patients require further treatment
with either a repeat PTCA or coronary artery bypass surgery to
relieve the newly formed stenosis. Restenosis of a mechanically
damaged vessel is not a thrombotic process but instead is the
result of a hyperproliferative response in the surrounding smooth
muscle cells which over time results in a decreased luminal
diameter of the affected vessel due to increased muscle mass. Id.
As for arterial thrombosis, there is currently no effective
pharmacological treatment for the prevention of vascular restenosis
following mechanical recanalization.
[0012] Numerous strategies have been developed for the treatment of
thrombotic disorders. Many antithrombotic therapies are based on
interference in the hemostatic system. This approach carries the
inherent risk of bleeding, since the hemostatic system is no longer
fully responsive to potential injury. Therefore, antithrombotic
benefits are normally associated with antihemostatic risks. In
attempts to improve the benefit-to-risk ratio, antithrombotic
agents are continuously being developed. Various antithrombotic
strategies include administering general inhibitors of thrombin
formation such as heparin or vitamin K antagonists; administering
specific thrombin inhibitors; administering specific factor Xa
inhibitors; and administering inhibitors of platelet activation and
adhesion.
[0013] Evaluation of current antithrombotic strategies in terms of
antithrombotic benefits versus antihemostatic risks reveals that
the benefit-to-risk ratio tends to be more favorable for strategies
that interfere with one specific step rather than in a more general
phase of the hemostatic system [L. A. Harker, Biomedical Progress
vol 8, 1995, 17-26]. For example, the development of inhibitors
specific for factor Xa is an improvement from general and specific
thrombin inhibitors. But, this approach blocks the common
(intrinsic and extrinsic) pathway of thrombin generation (see FIG.
1), and thereby thrombin-dependent platelet activation. Thus, a
need exists for more specific anti-thrombotic agents that
selectively inhibit one single hemostatic pathway, while leaving
other pathways unaffected.
SUMMARY OF THE INVENTION
[0014] The present invention provides compounds of Formula (I or
X), pharmaceutical compositions, and methods for the treatment of
cardiovascular diseases. Embodiments of the present invention
provide compounds of Formula (I or X) as depicted below.
Embodiments of the present invention also provide methods for the
preparation of compounds of Formula (I or X) and pharmaceutical
compositions comprising compounds of Formula (I or X).
[0015] In another embodiment, the present invention provides
methods for the use of compounds of Formula (I or X) and
pharmaceutical compositions comprising compounds of Formula (I or
X) in treating human or animal disorders.
[0016] Compounds of Formula (I or X) may be useful as modulators of
the intrinsic clotting pathway by inhibiting the biological
activity of factor XI and/or both factor IX and factor XI.
Compounds of Formula (I or X) may be useful in a variety of
applications including management, treatment, control, and/or as an
adjunct of diseases in humans caused in part by the intrinsic
clotting pathway utilizing factor XI/IX. Such diseases or disease
states include cardiopulmonary bypass, stroke, myocardial
infarction, deep vein thrombosis associated with surgical
procedures or long periods of confinement, acute and chronic
inflammation and clotting associated with hemodialysis.
BRIEF DESCRIPTION OF THE FIGURES
[0017] The present invention will be described with reference to
the accompanying drawings, wherein:
[0018] FIG. 1 is a diagram depicting the steps involved in the
intrinsic and extrinsic blood clotting cascades, from time of
trauma to the activation of factor X.
[0019] FIG. 2 is a diagram depicting the steps following initial
intrinsic and extrinsic blood clotting cascades, beginning with the
formation of Xa and culminating in the formation of a thrombus.
DETAILED DESCRIPTION
[0020] Two blood coagulation pathways are associated with normal
hemostasis: intrinsic and extrinsic. These two coagulation pathways
converge in the formation of factor Xa (FIGS. 1&2). But, these
two coagulation pathways are interdependent because complete
elimination of the intrinsic pathway can lead to uncontrolled
bleeding. For example, Type B hemophiliacs completely lack factor
IX or factor IX function and have a phenotype characterized by a
severe bleeding disorder. Thus, the direct factor VIIa/tissue
factor activation of factor X, which bypasses the need for factor
VIII and factor IX, is insufficient for normal hemostasis.
Conversely, formation of the factor VIIIa/Ixa phospholipid factor X
activator (tenase complex) (20) is essential for normal
hemostasis.
[0021] Selective inhibition of the intrinsic pathway of coagulation
with a factor XI antagonist or a dual factor XI/IX antagonist can
provide a method to inhibit the clotting cascade associated with
some surgery, stroke, myocardial infarction and hemodialysis while
leaving the clotting pathway associated with external lesions such
as trauma or abscess intact. Factor XI and IX are primarily
associated with the intrinsic clotting pathway. Antagonists which
have activity to factor XI or dual activity to factor XI/IX may
have a therapeutic benefit in diseases associated with intrinsic
pathway clotting by inhibiting intravascular thrombosis.
Additionally, antagonists of factor XI or dual antagonists of
factor XI/IX may not have the side effect of unwanted or
uncontrollable bleeding by impairing extravascular hemostasis
associated with wound healing.
[0022] Some point mutations in factor IX partially inhibit its
function and result in a mild or moderate phenotype manifested as a
non-life threatening bleeding disorder [Bowen, D. J., J. Clin.
Pathol: Mol. Pathol. 55:1-18 (2002)]. These point mutations cause
factor IX to behave as if it were subject to a partial antagonist.
In the presence of a partial antagonist, factor IX should maintain
some activity, even at saturation levels of the partial antagonist.
As a result of the point mutations in factor IX, its activity is
reduced along with clotting associated with the intrinsic pathway,
but some residual activity remains that leaves the extrinsic
pathway intact. Additionally, an antibody directed against the
gamma-carboxyglutamic acid domain of Factor XI demonstrated
efficacy in animal models of thrombosis without an increase in
bleeding times [Refino, C. J., et al. Thromb Haemost. 82(3)
1188-1195 (1999)].
[0023] The present invention provides compounds of Formula (I or
X), pharmaceutical compositions, and methods to inhibit the
clotting activities of factor XI and/or both factor IX and factor
XI. Inhibition of hemostasis with agents that may selectively
inhibit the intrinsic pathway of factor X activation may leave the
extrinsic pathway intact and allow the formation of small, but
hemostatically important amounts of factor Xa and thrombin.
[0024] Embodiments of the present invention provide compounds of
Formula (I or X) as depicted below. Embodiments of the present
invention also provide methods of the preparation of compounds of
Formula (I or X) and pharmaceutical compositions comprising
compounds of Formula (I or X).
[0025] In another embodiment, the present invention provides
methods for the use of compounds of Formula (I or X) and
pharmaceutical compositions comprising compounds of Formula (I or
X) in treating human or animal disorders. Compounds of the Formula
(I or X) may be useful as modulators of the intrinsic clotting
pathway by inhibiting the biological activities of factor XI and/or
both factor IX and factor XI. Compounds of Formula (I or X) may be
useful in a variety of applications including management,
treatment, control, and/or as an adjunct of diseases in humans
caused in part by the intrinsic clotting pathway utilizing factors
XI/IX. Such diseases or disease states include cardiopulmonary
bypass, stroke, myocardial infarction, deep vein thrombosis
associated with surgical procedures or long periods of confinement,
acute and chronic inflammation and clotting associated with
hemodialysis.
[0026] In a first aspect, the present invention provides a compound
comprising at least one moiety of the Formula (I or X).
[0027] In one aspect, the present invention provides compounds
which are represented by Formula I: Ar.sub.2--K (I) wherein
[0028] Ar.sub.2 comprises an aryl, heteroaryl, fused
cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl,
or fused heterocyclylheteroaryl group optionally substituted 1 to 7
times. In an embodiment, Ar.sub.2 comprises an aryl, heteroaryl, or
fused arylheterocyclyl group optionally substituted 1 to 7 times.
In another embodiment, Ar.sub.2 comprises a phenyl, naphthyl,
pyridyl, indolyl, isoquinolyl, pyrimidyl, tetrahydroisoquinolyl,
quinoxazoyl, or quinazolyl group optionally substituted 1 to 7
times. In another embodiment, Ar.sub.2 comprises a substituted
phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl,
2-quinazolyl, or 3-tetrahydroisoquinolyl group having 1 to 5
substituents wherein the substituents independently comprise:
[0029] a) -fluoro;
[0030] b) -chloro;
[0031] c) -bromo;
[0032] d) -iodo;
[0033] e) -cyano;
[0034] f) -nitro;
[0035] g) -perfluoroalkyl;
[0036] h) -T.sub.1-R.sub.20;
[0037] i) -alkyl;
[0038] j) -aryl;
[0039] k) -heteroaryl;
[0040] l) -heterocyclyl;
[0041] m) -cycloalkyl;
[0042] n) -alkylene-aryl;
[0043] o) -alkylene-arylene-aryl;
[0044] p) -alkylene-arylene-alkyl;
[0045] q) -arylene-alkyl;
[0046] r) -arylene-aryl;
[0047] s) -arylene-heteroaryl;
[0048] t) -heteroarylene-aryl;
[0049] u) -heteroarylene-heteroaryl;
[0050] v) -heteroarylene-heterocyclyl;
[0051] w) -arylene-heterocyclyl;
[0052] x) -arylene-arylene-alkyl;
[0053] y) -T.sub.1-alkyl;
[0054] z) -T.sub.1-aryl;
[0055] aa) -T.sub.1-alkylene-aryl;
[0056] bb) -T.sub.1-alkenylene-aryl;
[0057] cc) -T.sub.1-alkylene-heteroaryl;
[0058] dd) -T.sub.1-alkenylene-heteroaryl;
[0059] ee) -T.sub.1-cycloalkylene-aryl;
[0060] ff) -T.sub.1-cycloalkylene-heteroaryl;
[0061] gg) -T.sub.1-heterocyclylene-aryl;
[0062] hh) -T.sub.1-heterocyclylene-heteroaryl;
[0063] ii) -T.sub.1-arylene-alkyl;
[0064] jj) -T.sub.1-arylene-alkenyl;
[0065] kk) -T.sub.1-alkylene-arylene-aryl;
[0066] ll) -T.sub.1-arylene-T.sub.2-aryl;
[0067] mm) -T.sub.1-arylene-arylene-aryl;
[0068] nn) -T.sub.1-alkylene-arylene-alkyl;
[0069] oo) -alkylene-T.sub.1-alkylene-aryl;
[0070] pp) -arylene-T.sub.1-alkyl;
[0071] qq) -arylene-T.sub.1-alkylene-aryl;
[0072] rr) -T.sub.1-alkylene-T.sub.2-aryl;
[0073] ss) -T.sub.1-alkylene-aryl;
[0074] tt) -alkylene-T.sub.1-heteroaryl;
[0075] uu) -alkylene-T.sub.1-cycloalkyl;
[0076] vv) -alkylene-T.sub.1-heterocyclyl;
[0077] ww) -alkylene-T-arylene-alkyl;
[0078] xx) -alkylene-T.sub.1-alkylene-arylene-alkyl;
[0079] yy) -alkylene-T.sub.1-alkyl;
[0080] zz) -alkylene-T.sub.1-R.sub.20;
[0081] aaa) -arylene-T.sub.1-R.sub.20;
[0082] bbb) -alkylene-cycloalkyl;
[0083] ccc) -T.sub.1-arylene-T.sub.2-alkylene-aryl;
[0084] ddd) -T.sub.1-arylene-aryl;
[0085] eee) -T.sub.1-alkylene-cycloalkyl;
[0086] fff) -T.sub.1-cycloalkyl;
[0087] ggg) -T.sub.1-heterocyclyl-T.sub.2-aryl;
[0088] hhh) -T.sub.1-alkynyl;
[0089] iii) -T.sub.1-alkylene-T.sub.2-alkyl; or
[0090] jjj) -hydrogen; wherein T.sub.1 comprises --CH.sub.2--,
--O--, --N(R.sub.21)--, --C(O)--, --CON(R.sub.21)--,
--N(R.sub.21)C(O)--, --N(R.sub.21)CON(R.sub.22)--,
--N(R.sub.21)C(O)O--, --OC(O)N(R.sub.21)--,
--N(R.sub.21)SO.sub.2--, --SO.sub.2N(R.sub.21)--, --C(O)--O--,
--O--C(O)--, --S--, --S(O)--, --S(O.sub.2)--,
--N(R.sub.21)SO.sub.2N(R.sub.22)--, ##STR1## and wherein R.sub.20,
R.sub.21, R.sub.22 and R.sub.23, independently comprise: -hydrogen,
-alkyl, -alkenyl, -alkylene-cycloalkyl, -alkynene-heterocyclyl,
-aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl,
-alkylene-arylene-alkyl, -alkylene-arylene-aryl,
-alkylene-arylene-alkylene-aryl, -alkylene-arylene-O-arylene, or
alkylene-arylene-O-alkylene-aryl; and wherein T.sub.2 comprises a
direct bond, --CH.sub.2--, --O--, --N(R.sub.24)--, --C(O)--,
--CON(R.sub.24)--, --N(R.sub.24)C(O)--,
--N(R.sub.24)CON(R.sub.25)--, --N(R.sub.24)C(O)O--,
--OC(O)N(R.sub.24)--, --N(R.sub.24)SO.sub.2--,
--SO.sub.2N(R.sub.24)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O.sub.2)--, --N(R.sub.24)SO.sub.2N(R.sub.25)--, wherein
R.sub.24 and R.sub.25 independently comprise; -hydrogen, -alkyl,
-alkenyl, -alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl,
-heteroaryl, -arylene-alkyl, -alkylene-aryl, and
-alkylene-arylene-alkyl.
[0091] In another embodiment, Ar.sub.2 comprises a substituted
phenyl, 2-naphthyl, 2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or
2-quinazolyl group having 1 to 5 substituents independently
comprising:
a) -fluoro;
b) -chloro;
c) -bromo;
d) -iodo;
e) -cyano;
f) -nitro;
g) -perfluoroalkyl;
h) -T.sub.1-R.sub.20;
i) -alkyl;
j) -aryl;
k) -arylene-alkyl;
l) -T.sub.1-alkyl;
m) -T.sub.1-alkylene-aryl;
n) -T.sub.1-alkylene-arylene-aryl;
o) -T.sub.1-alkylene-arylene-alkyl;
p) -arylene-T.sub.1-alkyl; or
q) -hydrogen;
wherein T.sub.1 comprises --CH.sub.2--, --O--, --N(R.sub.21)--,
--CON(R.sub.21)--, or --N(R.sub.21)C(O)--; wherein R.sub.20 and
R.sub.21 independently comprise: -hydrogen, -alkyl, or -aryl.
[0092] K comprises a group of the formula ##STR2## wherein
[0093] c is equal to 0, 1, or 2; wherein the values of 0, 1, and 2
comprise a direct bond, --CH.sub.2--, and --CH.sub.2--CH.sub.2--,
optionally substituted 1 to 4 times with a substituent group,
wherein said substituent group(s) or the term substituted refers to
groups comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl,
-alkylene-arylene-alkyl, --O-alkyl, --O-aryl, or -hydroxyl. In an
embodiment, c is equal to 0 or 1. In another embodiment, c is equal
to 0.
[0094] G comprises: -hydrogen, --CO.sub.2R.sub.1,
--CH.sub.2OR.sub.1, --C(O)--R.sub.1,
--C(R.sub.1X).dbd.N--O--R.sub.2, --C(O)N (R.sub.1)(R.sub.2),
--C(O)--NH--NH.sub.2, an acid isostere, or an ester isostere,
wherein R.sub.1 and R.sub.2 independently comprise: -hydrogen,
-alkyl, alkoxy, alkylhydroxy, alkyl-N,N'-dialkyl-amino,
alkyl-amino-acyl, -aryl, -arylene-alkyl, -alkylene-aryl,
-alkylene-arylene-alkyl, or when R.sub.1 and R.sub.2 are bonded to
a nitrogen group in G, Rag and R.sub.2 may be taken together to
form a ring having the formula
--(CH.sub.2).sub.m-Z.sub.2-(CH.sub.2).sub.n, wherein m and n are,
independently, 1, 2, 3, or 4; Z.sub.2 comprises --CH.sub.2--,
--C(O)--, --O--, --N(H)--, --S--, --S(O)--, --S(O.sub.2)--,
--CON(H)--, --NHC(O)--, --NHC(O)N(H)--, --NH(SO.sub.2)--,
--S(O.sub.2)N(H)--, --(O)CO--, --NHS(O.sub.2)NH--, --OC(O)--,
--N(R.sub.24)--, --N(C(O)R.sub.24)--, --N(C(O)NHR.sub.12)--,
--N(S(O.sub.2)NHR.sub.24)--, --N(SO.sub.2R.sub.24)--, or
--N(C(O)OR.sub.24)--; wherein R.sub.24 comprises hydrogen, aryl,
alkyl, or alkylene-aryl. In an embodiment, G comprises: -hydrogen,
--CO.sub.2R.sub.1, --CH.sub.2OR.sub.1, --C(O)--R.sub.1,
--C(R.sub.1).dbd.N--O--R.sub.2, or an acid isostere; wherein
R.sub.1 and R.sub.2 independently comprise: -hydrogen, -alkyl,
-aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl.
In another embodiment, G comprises: -hydrogen or --CO.sub.2R.sub.1;
wherein R.sub.1 comprises: -hydrogen, -alkyl, or -aryl. In another
embodiment, G comprises: -hydrogen or --CO.sub.2H. In another
embodiment, G comprises: --CO.sub.2R.sub.1 or an ester isostere,
wherein R.sub.1 comprises -alkyl, -alkylene-aryl, or -aryl.
[0095] R.sub.3 comprises: hydrogen, -alkyl, alkylene-aryl, -aryl,
or -alkylene-cycloalkyl. In an embodiment, R.sub.3 comprises:
hydrogen. In another embodiment, R.sub.3 comprises: -alkyl,
alkylene-aryl, or -alkylene-cycloalkyl.
[0096] R.sub.4 comprises: hydrogen, -alkyl, -alkylene-cycloalkyl,
or -alkylene-heterocyclyl, -alkylene. R.sub.5 comprises: hydrogen,
-alkyl, -alkylene-cycloalkyl, -alkylene-heterocyclyl, -alkoxy,
alkylhydroxy, alkyl-N,N'-dialkyl-amino, or -alkyl-amino-acyl. In an
embodiment, R.sub.4 comprises: hydrogen, and R.sub.5 comprises:
alkyl, -alkoxy, alkylhydroxy, or -alkylene-cycloalkyl.
[0097] J.sub.1, J.sub.2, J.sub.3, J.sub.4, J.sub.5 independently
comprise --C(R.sub.25)(R.sub.26)-- or a direct bond, wherein
R.sub.25 and R.sub.26 independently comprise hydrogen, -alkyl,
-aryl, -alkylene-aryl, alkoxy, alkylhydroxy, alkylene-O-alkyl,
alkylene-O-alkylene-aryl, --CO.sub.2H, -alkylene-CO.sub.2H,
--CO.sub.2-alkyl, or -alkylene-CO.sub.2-alkyl, -acid isostere, or
-ester isostere, and wherein the ring comprising nitrogen and
J.sub.1 through J.sub.5 contains at least four carbon atoms and at
least one of J.sub.1 through J.sub.5 is substituted with
--CO.sub.2H, -alkylene-CO.sub.2H, --CO.sub.2-alkyl, or
-alkylene-CO.sub.2-alkyl, -acid isostere, or -ester isostere.
[0098] Z.sub.1 comprises --CH.sub.2--, --C(O)--, --O--, --N(H)--,
--S--, --S(O)--, --S(O.sub.2)--, --CON(H)--, --NHC(O)--,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O.sub.2)N(H)--, --(O)CO--,
--NHS(O.sub.2)NH--, --OC(O)--, --N(R.sub.6)--, --N(C(O)R.sub.6)--,
--N(C(O)NHR.sub.6)--, --N(S(O.sub.2)NHR.sub.6)--,
--N(SO.sub.2R.sub.6)--, or --N(C(O)OR.sub.6)--; wherein R.sub.6
comprises: -hydrogen, alkyl, aryl, or alkylene-aryl. In an
embodiment, Z.sub.1 comprises --CH.sub.2--, --O--, --N(H)--, --S--,
--S(O.sub.2)--, --N(R.sub.6)--, or --N(C(O)OR.sub.6)--, wherein
R.sub.6 comprises alkyl or alkylene-aryl.
[0099] V comprises: --(CH.sub.2).sub.b--S--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--S--, --S--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--S(O.sub.2)--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--S(O.sub.2)--, --S(O.sub.2)--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--O--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--N(R.sub.7)--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--O--, --(CH.sub.2).sub.b--N(R.sub.7),
--(CH.sub.2).sub.a--, or a direct bond; in which a is equal to 0,
1, or 2, b is equal to 1 or 2, and R.sub.7 comprises: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl; wherein the values of 0, 1, and 2 comprise
a direct bond, --CH.sub.2--, and --CH.sub.2--CH.sub.2--, optionally
substituted 1 to 4 times with a substituent group, wherein said
substituent group(s) or the term substituted refers to groups
comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl,
-alkylene-arylene-alkyl, --O-alkyl, --O-aryl, or -hydroxyl. In an
embodiment, V comprises: --(CH.sub.2).sub.b--O--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--N(R.sub.7)--(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--O--, --(CH.sub.2).sub.b--N(R.sub.7),
--(CH.sub.2).sub.a--, or a direct bond; in which a is equal to 0,
1, or 2, b is equal to 1 or 2, and R.sub.7 comprises: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl; wherein the values of 0, 1, and 2 comprise
a direct bond, --CH.sub.2--, and --CH.sub.2--CH.sub.2--, optionally
substituted 1 to 4 times with a substituent group, wherein said
substituent group(s) or the term substituted refers to groups
comprising: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl,
-alkylene-arylene-alkyl, --O-alkyl, --O-aryl, or -hydroxyl. In
another embodiment, V comprises: --(CH.sub.2).sub.a--,
--(CH.sub.2).sub.b--O--(CH.sub.2).sub.a--, or a direct bond,
wherein a is equal to 1 or 2, and b is equal to 1. In another
embodiment, V comprises: --(CH.sub.2).sub.a-- or a direct bond,
wherein a is equal to 1.
[0100] X comprises: --N(R.sub.8)--, --CON(R.sub.8)--,
--N(R.sub.8)CO--, --N(R.sub.8)CON(R.sub.9)--, --OC(O)N(R.sub.8)--,
--SO.sub.2N(R.sub.8)--, or --N(R.sub.8)SO.sub.2N(R.sub.9)--;
wherein R.sub.8 and R.sub.9 independently comprise: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,
-alkylene-arylene-alkyl,
-alkylene-cycloalkylene-C(O)-alkylene-aryl,
-alkylene-heterocyclylene-C(O)-alkylene-aryl,
-alkylene-C(H)(R.sub.10)(R.sub.11),
-alkylene-N--(R.sub.10)(R.sub.11), or -alkylene-cycloalkyl, [0101]
wherein R.sub.10 comprises H, alkyl, alkylene-aryl,
alkylene-heteroaryl, aryl, or heteroaryl, and R.sub.11 comprises H,
-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -aryl, -heteroaryl,
--C(O)--O-alkyl, --C(O)--O-alkylene-aryl,
--C(O)--O-alkylene-heteroaryl, --C(O)-alkyl, --C(O)-alkylene-aryl,
--C(O)-alkylene-heteroaryl, --S(O).sub.2-alkyl, --S(O).sub.2-aryl,
--S(O).sub.2-heteroaryl, --S(O).sub.2-alkylene-aryl,
--S(O).sub.2-alkylene-heteroaryl, --S(O).sub.2--NH-alkyl,
--S(O).sub.2--NH-alkylene-aryl,
--S(O).sub.2--NH-alkylene-heteroaryl, --S(O).sub.2--NH-aryl, or
--S(O).sub.2--NH-heteroaryl; [0102] R.sub.10 and R.sub.11 may be
taken together to form a ring having the formula
--(CH.sub.2).sub.m-Z.sub.2-(CH.sub.2).sub.n-- bonded to the
nitrogen or carbon atom to which R.sub.10 and R.sub.11 are
attached, wherein m and n are, independently, 1, 2, 3, or 4;
Z.sub.2 independently comprises --CH.sub.2--, --C(O)--, --O--,
--N(H)--, --S--, --S(O)--, --S(O.sub.2)--, --CON(H)--, --NHC(O)--,
--NHC(O)N(H)--, --NH(SO.sub.2)--, --S(O.sub.2)N(H)--, --(O)CO--,
--NHS(O.sub.2)NH--, --OC(O)--, --N(R.sub.12)--,
--N(C(O)R.sub.12)--, --N(C(O)NHR.sub.12)--,
--N(S(O.sub.2)NHR.sub.12)--, --N(SO.sub.2R.sub.12)--, or
--N(C(O)OR.sub.12)--; or [0103] R.sub.10 and R.sub.11 may be taken
together, with the nitrogen or carbon atom to which they are
attached, to form a heterocyclyl or heteroaryl ring. [0104]
R.sub.12 comprises hydrogen, aryl, alkyl, or alkylene-aryl;
[0105] In an embodiment, X comprises: --N(R.sub.8)--,
--CON(R.sub.8)--, --N(R.sub.8)CO--, or --N(R.sub.8)CON(R.sub.9)--,
wherein R.sub.8 and R.sub.9 independently comprise: -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl. In another embodiment, X comprises:
--N(R.sub.8)--, --CON(R.sub.8)--, or --N(R.sub.8)CO--, wherein
R.sub.8 comprises: -hydrogen, -alkyl, -aryl, -arylene-alkyl,
-alkylene-aryl, or -alkylene-arylene-alkyl. In another embodiment,
X comprises --CON(R.sub.8)--, wherein R.sub.8 comprises -hydrogen,
-alkyl, -aryl, -arylene-alkyl, -alkylene-aryl,
-alkylene-arylene-alkyl, or -alkylene-cycloalkyl,
[0106] Ar.sub.1 comprises an aryl, heteroaryl, fused
cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl,
or fused heterocyclylheteroaryl group optionally substituted 1 to 7
times. In an embodiment, Ar.sub.1 comprises a mono- or bicyclic
aryl or heteroaryl group optionally substituted 1 to 7 times. In
another embodiment, Ar.sub.1 comprises a phenyl, pyridyl, indolyl,
naphthyl, thiophenyl, thiazole, or benzothiazole group optionally
substituted 1 to 7 times. In another embodiment, Ar.sub.1 comprises
a phenyl group having 1 to 5 substituents, wherein the substituents
independently comprise:
a) -fluoro;
b) -chloro;
c) -bromo;
d) -iodo;
e) -cyano;
f) -nitro;
g) -perfluoroalkyl;
h) -D.sub.1-R.sub.14;
i) -alkyl;
j) -aryl;
k) -heteroaryl;
l) -heterocyclyl;
m) -cycloalkyl;
n) -alkylene-aryl;
o) -alkylene-heteroaryl;
p) -alkylene-arylene-D.sub.1-R.sub.14;
q) -alkylene-heteroarylene-D.sub.1-R.sub.14;
r) -alkylene-arylene-aryl;
s) -alkylene-heteroarylene-aryl;
t) -alkylene-arylene-heteroaryl;
u) -alkylene-arylene-arylene-D.sub.1-R.sub.14;
v) -alkylene-arylene-alkyl;
w) -alkylene-heteroarylene-alkyl;
x) y) -arylene-cycloalkyl;
z) -heteroarylene-alkyl;
aa) -arylene-arylene-alkyl;
bb) -D.sub.1-alkyl;
cc) -D.sub.1-aryl;
dd) -D.sub.1-heteroaryl;
ee) -D.sub.1-arylene-D.sub.2-R.sub.14;
ff) -D.sub.1-heteroarylene-D.sub.2-R.sub.14;
gg) -D.sub.1-alkylene-heteroaryl;
hh) -D.sub.1-alkylene-aryl;
ii) -D.sub.1-alkylene-arylene-D.sub.2-R.sub.14
jj) -D.sub.1-alkylene-heteroarylene-D.sub.2-R.sub.14
kk) -D.sub.1-arylene-alkyl;
ll) -D.sub.1-heteroarylene-alkyl;
mm) -D.sub.1-alkylene-arylene-aryl;
nn) -D.sub.1-alkylene-heteroarylene-aryl;
oo) -D.sub.1-arylene-arylene-aryl;
pp) -D.sub.1-alkylene-arylene-alkyl;
qq) -D.sub.1-alkylene-heteroarylene-alky
ss) -alkylene-D.sub.1-alkylene-aryl;
tt) -alkylene-D.sub.1-alkylene-arylene-D.sub.2-R.sub.14
uu) -arylene-D.sub.1-alkyl;
vv) -arylene-D.sub.1-cycloalkyl;
ww) -arylene-D.sub.1-heterocyclyl;
xx) -alkylene-D.sub.1-aryl;
yy) -alkylene-D.sub.1-heteroaryl;
zz) -alkylene-D.sub.1-arylene-D.sub.2-R.sub.14
aaa) -alkylene-D.sub.1-heteroarylene-D.sub.2-R.sub.14
bbb) -alkylene-D.sub.1-heteroaryl;
ccc) -alkylene-D.sub.1-cycloalkyl;
ddd) -alkylene-D.sub.1-heterocyclyl;
eee) -alkylene-D.sub.1-arylene-alkyl;
fff) -alkylene-D.sub.1-heteroarylene-alkyl;
ggg) -alkylene-D.sub.1-alkylene-arylene-alkyl;
hh) -alkylene-D.sub.1-alkylene-heteroarylene-alkyl;
iii) -alkylene-D.sub.1-alkyl;
jjj) -alkylene-D.sub.1-R.sub.14;
kkk) -arylene-D.sub.1-R.sub.14;
lll) -heteroarylene-D.sub.1-R.sub.14;
mmm) -D.sub.1-alkynyl;
nnn) -D.sub.1-alkylene-cycloalkyl;
ooo) -arylene-D.sub.1-arylene-D.sub.2-R.sub.14 or
ppp) -hydrogen;
[0107] wherein D.sub.1 comprises --CH.sub.2--, -alkylene-,
-alkenylene-, -alkylene-S--, --S-alkylene-, -alkylene-O--,
--O-alkylene-, -alkylene-S(O).sub.2--, --S(O).sub.2-alkylene,
--O--, --N(R.sub.15)--, --C(O)--, --CON(R.sub.15)--,
--N(R.sub.15)C(O)--, --N(R.sub.15)CON(R.sub.16)--,
--N(R.sub.15)C(O)O--, --OC(O)N(R.sub.15)--,
--N(R.sub.15)SO.sub.2--, --SO.sub.2N(R.sub.15)--, --C(O)--O--,
--O--C(O)--, --S--, --S(O)--, --S(O.sub.2)--,
--N(R.sub.15)SO.sub.2N(R.sub.16)--, ##STR3## and wherein R.sub.14,
R.sub.15, R.sub.16, and R.sub.17 independently comprise: -hydrogen,
-alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl,
-alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or
-alkylene-heteroarylene-alkyl. D.sub.2 comprises --CH.sub.2--,
-alkylene-, -alkenylene-, -alkylene-S--, --S-alkylene-,
-alkylene-O--, --O-alkylene-, -alkylene-S(O).sub.2--,
--S(O).sub.2-alkylene, --O--, --N(R.sub.18)--, --C(O)--,
--CON(R.sub.18)--, --N(R.sub.18)C(O)--,
--N(R.sub.18)CON(R.sub.19)--, --N(R.sub.18)C(O)O--,
--OC(O)N(R.sub.18)--, --N(R.sub.18)SO.sub.2--,
--SO.sub.2N(R.sub.18)--, --C(O)--O--, --O--C(O)--, --S--, --S(O)--,
--S(O.sub.2)--, --N(R.sub.18)SO.sub.2N(R.sub.19)--, and wherein
R.sub.18 and R.sub.19 independently comprise: -hydrogen, -alkyl,
-aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl.
[0108] In another embodiment, Ar.sub.1 comprises a mono-substituted
phenyl group wherein the substituent comprises: -aryl,
-arylene-alkyl, -D.sub.1-aryl, -D.sub.1-alkylene-arylene-alkyl, or
-arylene-D.sub.1-alkyl; wherein D.sub.1 comprises --O--,
--N(R.sub.15)--, --CON(R.sub.15)--, or --N(R.sub.15)C(O)--, and
wherein R.sub.15 comprises: -hydrogen; -alkyl; or -aryl.
[0109] In another embodiment, Ar.sub.1 comprises a phenyl group
substituted with at least one of the following substituents:
[0110] a) -D.sub.1-R.sub.14;
[0111] b) -alkyl;
[0112] c) -aryl;
[0113] d) -heteroaryl;
[0114] e) -heterocyclyl;
[0115] f) -arylene-alkyl;
[0116] g) -D.sub.1-alkyl;
[0117] h) -D.sub.1-aryl;
[0118] i) -D.sub.1-heteroaryl;
[0119] j) -D.sub.1-arylene-D.sub.2-R.sub.14;
[0120] k) -D.sub.1-alkylene-heteroaryl;
[0121] l) -D.sub.1-alkylene-aryl;
[0122] m) -D.sub.1-alkylene-arylene-D.sub.2-R.sub.14
[0123] n) -arylene-D.sub.1-alkyl;
[0124] o) -alkylene-D.sub.1-alkyl;
[0125] p) -alkylene-D.sub.1-R.sub.14;
[0126] q) -arylene-D.sub.1-R.sub.14;
[0127] r) -D.sub.1-alkynyl;
[0128] s) -D.sub.1-alkylene-cycloalkyl;
[0129] t) -arylene-D.sub.1-arylene-D.sub.2-R.sub.14 [0130] wherein
[0131] D.sub.1 and D.sub.2 independently comprise: --O-- or
--S(O.sub.2)--, and [0132] R.sub.14 comprises hydrogen, -alkyl,
-aryl, -arylene-aryl, -alkylene-aryl. In another embodiment,
Ar.sub.1 comprises an unsubstituted phenyl or biphenyl group.
[0133] The alkyl, aryl, heteroaryl, alkylene, and arylene groups in
Ar.sub.1, Ar.sub.2, R.sub.1 through R.sub.26 may be optionally
substituted 1 to 4 times with a substituent group, wherein said
substituent group(s) or the term substituted refers to groups
comprising:
a) -hydrogen;
b) -fluoro;
c) -chloro;
d) -bromo;
e) -iodo;
f) -cyano;
g) -nitro;
h) -perfluoroalkyl;
i) -Q-perfluoroalkyl
j) -Q-R.sub.27;
k) -Q-alkyl;
l) -Q-aryl;
m) -Q-alkylene-aryl;
n) -Q-alkylene-NR.sub.27R.sub.28; or
o) -Q-alkyl-W--R.sub.28;
[0134] wherein Q and W independently comprise: --CH.sub.2--, --O--,
--N(R.sub.29)--, --C(O)--, --CON(R.sub.29)--, --N(R.sub.29)C(O)--,
--N(R.sub.29)CON(R.sub.30)--, --N(R.sub.29)C(O)O--,
--OC(O)N(R.sub.29)--, --N(R.sub.29)SO.sub.2--,
--SO.sub.2N(R.sub.29)--, --C(O)--O--, --O--C(O)--, or
--N(R.sub.29)SO.sub.2N(R.sub.30)--, wherein R.sub.27, R.sub.28,
R.sub.29, and R.sub.30 independently comprise: -hydrogen, -alkyl,
-aryl, -arylene-alkyl, -alkylene-aryl, or
-alkylene-arylene-alkyl.
[0135] In another embodiment, the compounds are represented by
Formula (I), in which c is equal to 0; G comprises: -hydrogen or
--CO.sub.2H; V comprises: --CH.sub.2-- or a direct bond; X
comprises: --CON(R.sub.8)--, or --N(R.sub.8)CO-- wherein R.sub.8
comprises: -hydrogen; Ar.sub.1 comprises a mono-substituted phenyl
group wherein the substituent comprises: -aryl, -arylene-alkyl,
-D.sub.1-aryl -D.sub.1-alkylene-arylene-alkyl, or
-arylene-D.sub.1-alkyl, wherein D.sub.1 comprises --O--, or
--N(R.sub.15)--, wherein R.sub.15 comprises: -hydrogen, -alkyl, or
-aryl; and Ar.sub.2 comprises a substituted phenyl, 2-naphthyl,
2-pyridyl, 3-isoquinolyl, 2-pyrimidyl or 2-quinazolyl group having
1 to 5 substituents independently comprising: -hydrogen, -fluoro,
-chloro, -bromo, iodo, -cyano, -nitro, -perfluoroalkyl,
-T.sub.1-R.sub.14, -alkyl, -aryl, -arylene-alkyl, -T.sub.1-alkyl,
-T.sub.1-alkylene-aryl, -T.sub.1-alkylene-arylene-aryl,
-T.sub.1-alkylene-arylene-alkyl, or -arylene-T.sub.1-alkyl; wherein
T.sub.1 comprises --CH.sub.2--, --O--, --N(R.sub.21)--,
--CON(R.sub.21)--, or --N(R.sub.21)C(O)--; wherein R.sub.21
comprises: -hydrogen, -alkyl, or -aryl. The alkyl, aryl, alkylene,
and arylene groups in Ar.sub.1, and Ar.sub.2 may be optionally
substituted 1 to 4 times with a substituent group, wherein said
substituent group(s) or the term substituted refers to groups
comprising: -hydrogen, -fluoro, -chloro, -bromo, iodo, -cyano,
-nitro, or -perfluoroalkyl.
[0136] In another embodiment, the instant invention relates to a
compound of Formula (X), ##STR4## wherein R.sub.101 is selected
from the group consisting of --H, or --CH.sub.2-thienyl wherein the
thienyl group in --CH.sub.2-thienyl is optionally substituted with
--Br or --CH.sub.3; R.sub.102 is selected from the group consisting
of --C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, -thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of --H, --CH.sub.3, --CF.sub.3, --Cl, --Br, --F, --C(O)CH.sub.3,
--CH.sub.2CH.sub.3, --CH.dbd.CH.sub.2, --CH.sub.2OH,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.3, -propenyl,
-3,3-dimethyl-butenyl, -isopropenyl, -phenyl, -phenylene-methyl,
-phenylene-propyl, -phenylene-trifluoromethyl, -phenylene-chloride,
-cyclopentyl, -cyclopentenyl, and -furanyl; R.sub.104 is selected
from the group consisting of --O-cyclohexylene-ethyl,
--O-cyclohexylene-t-butyl, --O-cyclohexylene-1-propyl,
--O-phenylene-t-butyl, -phenylene-t-butyl, and
--C(O)-phenylene-t-butyl; and Y is selected from the group
consisting of --H, -methylene-cyclopentyl, -amino-cyclohexyl,
-methylene-thienylene-methyl, methylene-thienylene-bromide, and
tetrahydropyranyl; or a pharmaceutically acceptable salt, ester, or
prodrug thereof.
[0137] In another embodiment, the instant invention relates to a
compound of Formula (X), ##STR5## wherein R.sub.101 is selected
from the group consisting of --H, or --CH.sub.2-thienyl wherein the
thienyl group in --CH.sub.2-thienyl is optionally substituted with
--Br or --CH.sub.3; R.sub.102 is selected from the group consisting
of --C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of --H, --CH.sub.3, --CF.sub.3, --Cl, --Br, --F, --C(O)CH.sub.3,
--CH.sub.2CH.sub.3, --CH.dbd.CH.sub.2, --CH.sub.2OH,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.3, -propenyl,
-3,3-dimethyl-butenyl, -isopropenyl, -phenyl, -phenylene-methyl,
phenylene-trifluoromethyl, -phenylene-chloride, cyclopentyl,
cyclopentenyl, and furanyl; R.sub.104 is selected from the group
consisting of --O-cyclohexylene-ethyl, --O-cyclohexylene-t-butyl,
--O-cyclohexylene-1-propyl, --O-phenylene-t-butyl,
-phenylene-t-butyl, and --C(O)-phenylene-t-butyl; and Y is selected
from the group consisting of --H, -methylene-cyclopentyl,
-amino-cyclohexyl, -methylene-thienylene-methyl,
methylene-thienylene-bromide, and tetrahydropyranyl; or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
[0138] The instant invention also relates to a compound of Formula
(X), ##STR6## wherein R.sub.101 is selected from the group
consisting of --H, or --CH.sub.2-thienyl wherein the thienyl group
in --CH.sub.2-thienyl is optionally substituted with --Br or
--CH.sub.3; R.sub.102 is selected from the group consisting of
--C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of --H, --CH.sub.3, --CF.sub.3, --Cl, --Br, --F, --C(O)CH.sub.3,
--CH.sub.2CH.sub.3, --CH.dbd.CH.sub.2--CH.sub.2OH,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.3, ##STR7##
R.sub.104 is selected from the group consisting of ##STR8## and Y
is selected from the group consisting of H, ##STR9## or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
[0139] Another embodiment is a compound wherein R.sub.104 is
##STR10## and wherein R.sub.103 is optionally substituted
--CH.sub.2-2-yl-thienyl or optionally substituted
--CH.sub.2-phenyl. Moreover, another embodiment relates to
compounds wherein R.sub.101 is --H and compounds wherein Y is
selected from the group consisting of ##STR11## Another embodiment
for Y is when it is -methylene-cyclopentyl.
[0140] In another embodiment, the instant invention relates to a
pharmaceutical composition comprising a therapeutically effective
amount of the compound of Formula (X) ##STR12## wherein R.sub.101
is selected from the group consisting of --H, or --CH.sub.2-thienyl
wherein the thienyl group in --CH.sub.2-thienyl is optionally
substituted with --Br or --CH.sub.3; R.sub.102 is selected from the
group consisting of --C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of ##STR13## R.sub.104 is selected from the group consisting of
##STR14## and Y is selected from the group consisting of H,
##STR15## or a pharmaceutically acceptable salt, ester, or prodrug
thereof, and one or more pharmaceutically acceptable carriers,
excipients, or diluents.
[0141] Other embodiments are pharmaceutical compositions wherein
R.sub.104 is ##STR16## and wherein R.sub.103 is optionally
substituted --CH.sub.2-2-yl-thienyl or optionally substituted
--CH.sub.2-phenyl. Another embodiment is when R.sub.103 is
optionally substituted --CH.sub.2-2-yl-thienyl.
[0142] Other embodiments are when the pharmaceutical composition
has a compound of formula (X) as above when R.sub.101 is H, or when
Y is selected from the group consisting of ##STR17## and more
particularly when Y is -methylene-cyclopentyl.
[0143] The present invention also relates to a method for the
inhibition of the normal biological function of factor IX
comprising administering to a subject a compound of Formula (X)
##STR18## wherein R.sub.101 is selected from the group consisting
of --H, or --CH.sub.2-thienyl wherein the thienyl group in
--CH.sub.2-thienyl is optionally substituted with --Br or
--CH.sub.3; R.sub.102 is selected from the group consisting of
--C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of ##STR19## R.sub.104 is selected from the group consisting of
##STR20## and Y is selected from the group consisting of H,
##STR21## or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
[0144] In another embodiment, the instant invention relates to a
method for the inhibition of the normal biological function of
factor IX, wherein the compound of formula (X) is delivered as part
of a pharmaceutical composition.
[0145] In another embodiment, the method for the inhibition of the
normal biological function of factor IX uses a compound of formula
(X) wherein R.sub.104 is ##STR22## or, wherein R.sub.103 is
optionally substituted --CH.sub.2-2-yl-thienyl or optionally
substituted --CH.sub.2-phenyl.
[0146] Another embodiment is the method for the inhibition of the
normal biological function of factor IX wherein a compound of
formula (X) is administered and R.sub.101 is --H. or wherein Y is
selected from the group consisting of ##STR23## Another method for
the inhibition of the normal biological function of factor IX is
administering a compound when Y is -methylene-cyclopentyl.
[0147] In another embodiment, the instant invention comprises a
method of treating stroke, myocardial infarction, an aneurysm, or
thrombosis comprising administering to a subject a compound of
Formula (X) ##STR24## wherein R.sub.101 is selected from the group
consisting of --H, or --CH.sub.2-thienyl wherein the thienyl group
in --CH.sub.2-thienyl is optionally substituted with --Br or
--CH.sub.3; R.sub.102 is selected from the group consisting of
--C(O)OH, --C(O)OCH.sub.3, --C(O)O-t-butyl,
--C(O)NH--OCH.sub.2-phenyl, --C(O)NHOH, and
--C(O)NHSO.sub.2CH.sub.3; R.sub.103 is selected from the group
consisting of --H, --CH.sub.2-thienyl, --CH.sub.2-phenyl,
--CH.sub.2-furanyl, thienyl, and benzothienyl wherein each of the
above possibilities for R.sub.103 except --H are optionally
substituted with one or more members selected from group consisting
of ##STR25## R.sub.104 is selected from the group consisting of
##STR26## and Y is selected from the group consisting of H,
##STR27## or a pharmaceutically acceptable salt, ester, or prodrug
thereof.
[0148] In another embodiment, the method of treating the
above-enumerated diseases comprises administering a compound of
formula (X) as part of a pharmaceutical composition. In another
embodiment, the method of treating the above-enumerated diseases
comprises administering a compound of formula (X) wherein R.sub.104
is ##STR28## or wherein R.sub.103 is optionally substituted
--CH.sub.2-2-yl-thienyl or optionally substituted
--CH.sub.2-phenyl. In an embodiment, R.sub.101 is --H.
[0149] One method of treating the above-enumerated diseases uses a
compound that is selected from the group consisting of [0150]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-phenyl-thiophen-2-yl)-propionic acid, [0151]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionic
acid, [0152]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline--
3-carbonyl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic
acid methyl ester, [0153]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid,
[0154]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid methyl
ester, [0155]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline--
3-carbonyl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid,
[0156]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbo-
nyl]-amino}-3-(5-furan-3-yl-thiophen-2-yl)-propionic acid, [0157]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-isopropyl-phenyl)-thiophen-2-yl]-propionic acid,
[0158]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline--
3-carbonyl]-amino}-3-(5-vinyl-thiophen-2-yl)-propionic acid, [0159]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-p-tolyl-thiophen-2-yl)-propionic acid, [0160]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-chloro-phenyl)-thiophen-2-yl]-propionic acid,
[0161]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-ethyl-thiophen-2-yl)-propionic acid, [0162]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-furan-2-yl-propionic acid, [0163]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(2-trifluoromethyl-phenyl)-propionic acid, [0164]
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid tert-butyl ester,
[0165]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(3,5-difluorophenyl)-propionic acid, [0166]
[[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(-
5-methyl-thiophen-2-ylmethyl)-amino]-acetic acid, [0167]
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester,
[0168]
{(4-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid, [0169]
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid, [0170]
Benzo[b]thiophen-3-yl-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoq-
uinoline-3-carbonyl]-amino}-acetic acid, [0171]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(4-fluoro-phenyl)-propionic acid, [0172]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propenyl-thiophen-2-yl)-propionic acid, [0173]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propyl-thiophen-2-yl)-propionic acid, [0174]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(3,3-dimethyl-but-1-enyl)-thiophen-2-yl]-propionic
acid, [0175]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline--
3-carbonyl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid
methyl ester, [0176]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid, [0177]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-methyl-thiophen-2-yl)-propionic acid, [0178]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid, [0179]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid, [0180]
3-(5-Bromo-thiophen-2-yl)-2(R)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid, [0181]
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-chloro-thiophen-2-yl)-propionic acid, [0182]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-chloro-furan-2-yl)-propionic acid, [0183]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(2,5-dichloro-thiophen-3-yl)-propionic acid, [0184]
(5-Bromo-thiophen-2-yl)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-is-
oquinoline-3-carbonyl]-amino}-acetic acid, [0185]
3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethy-
l-isoquinoline-3-carbonyl]-amino}-propionic acid, [0186]
3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-c-
yclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,
[0187]
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid, [0188]
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinol-
ine-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic
acid, [0189]
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-i-
soquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic
acid, [0190]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-furan-2-yl)-propionic acid, [0191]
2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-c-
arbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
[0192]
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid, [0193]
2(S)-{[7-(4-tert-Butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isop-
ropyl-thiophen-2-yl)-propionic acid, [0194]
2(S)-{[1-Cyclopentylmethyl-7-(4-trans-ethyl-cyclohexyloxy)-isoquinoline-3-
-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
[0195]
2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid, [0196]
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3--
carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,
[0197]
2(S)-{[6-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid, [0198]
2(S)-{[7-(4-tert-Butyl-phenyl)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid, [0199]
2(S)-{[7-(4-tert-Butyl-benzoyl)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid, [0200]
3-(5-Acetyl-thiophen-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylm-
ethyl-isoquinoline-3-carbonyl]-amino}-propionic acid, [0201]
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-(5-isopropyl-thiophen-2-ylmethyl)-2(R)-methanesulfonylamino-2-oxo-
-ethyl]-amide, [0202]
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-(5-isopropyl-thiophen-2-ylmethyl)-2(S)-methanesulfonylamino-2-oxo-
-ethyl]-amide, [0203]
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-benzyloxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide,
and [0204]
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-hydroxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide.
[0205] In another embodiment, the method of treating the
above-enumerated diseases comprises the administration of formula
(X) wherein Y is selected from the group consisting of ##STR29## In
another embodiment, the method of treating the above-enumerated
diseases comprises the administration of formula (X) wherein Y is
-methylene-cyclopentyl.
[0206] Also included within the scope of the invention are the
individual enantiomers of the compounds represented by Formula (I
or X) above as well as any wholly or partially racemic mixtures
thereof. The present invention also covers the individual
enantiomers of the compounds represented by formulas above as
mixtures with diastereoisomers thereof in which one or more
stereocenters are inverted.
[0207] Compounds of the present invention are listed in Table 1
below. TABLE-US-00001 TABLE 1 EX. Compound Name 1 ##STR30##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-phenyl-
thiophen-2-yl)-propionic acid 2 ##STR31## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-[5-(4- trifluoromethyl-phenyl)- thiophen-2-yl]-propionic
acid 3 ##STR32## 2(S)-{[7-(4-tert-Butyl- phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-cyclopent-1- enyl-thiophen-2-yl)- propionic acid methyl
ester 4 ##STR33## 2(S)-{[7-(4-tert-Butyl- phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-cyclopent-1- enyl-thiophen-2-yl)- propionic acid 5
##STR34## 2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-cyclopentyl-
thiophen-2-yl)-propionic acid methyl ester 6 ##STR35##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-cyclopentyl-
thiophen-2-yl)-propionic acid 7 ##STR36## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-furan-3-yl- thiophen-2-yl)-propionic acid 8 ##STR37##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-[5-(4-isopropyl-
phenyl)-thiophen-2-yl]- propionic acid 9 ##STR38##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-vinyl-thiophen-
2-yl)-propionic acid 10 ##STR39## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-p-tolyl- thiophen-2-yl)-propionic acid 11 ##STR40##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-[5-(4-chloro-
phenyl)-thiophen-2-yl]- propionic acid 12 ##STR41##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-ethyl-thiophen-
2-yl)-propionic acid 13 ##STR42## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-furan-2-yl- propionic acid 14 ##STR43##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(2-trifluoromethyl-
phenyl)-propionic acid 15 ##STR44## {(5-Bromo-thiophen-2-
ylmethyl)-[7-(4-tert-butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-acetic acid tert-butyl ester 16
##STR45## 2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(3,5- difluorophenyl)-propionic
acid 17 ##STR46## [[7-(4-tert-Butyl-phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]-(5- methyl-thiophen-2-
ylmethyl)-amino]-acetic acid 18 ##STR47## {(5-Bromo-thiophen-2-
ylmethyl)-[7-(4-tert-butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-acetic acid methyl ester 19
##STR48## {(4-Bromo-thiophen-2- ylmethyl)-[7-(4-tert-butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-acetic acid 20 ##STR49## {(5-Bromo-thiophen-2-
ylmethyl)-[7-(4-tert-butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-acetic acid 21 ##STR50##
Benzo[b]thiophen-3-yl-{[7- (4-tert-butyl-phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]- amino}-acetic acid 22
##STR51## 2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(4-fluoro-phenyl)- propionic
acid 23 ##STR52## 2(S)-{[7-(4-tert-Butyl- phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]- amino}-3-(5-propenyl-
thiophen-2-yl)-propionic acid 24 ##STR53## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-propyl- thiophen-2-yl)-propionic acid 25 ##STR54##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-[5-(3,3-dimethyl-
but-1-enyl)-thiophen-2-yl]- propionic acid 26 ##STR55##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-hydroxymethyl-
thiophen-2-yl)-propionic acid methyl ester 27 ##STR56##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-hydroxymethyl-
thiophen-2-yl)-propionic acid 28 ##STR57## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-methyl- thiophen-2-yl)-propionic acid 29 ##STR58##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-isopropenyl-
thiophen-2-yl)-propionic acid 30 ##STR59## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5- isopropylthiophen-2-yl)- propionic acid 31 ##STR60##
3-(5-Bromo-thiophen-2-yl)- 2(R)-{[7-(4-tert-butyl- phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]- amino}-propionic acid
32 ##STR61## 2(R)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-chloro-
thiophen-2-yl)-propionic acid 33 ##STR62## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-chloro-furan-2- yl)-propionic acid 34 ##STR63##
2(S)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(2,5-dichloro-
thiophen-3-yl)-propionic acid 35 ##STR64## (5-Bromo-thiophen-2-yl)-
{[7-(4-tert-butyl-phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-acetic acid 36 ##STR65##
3-(5-Bromo-furan-2-yl)-2(S)- {[7-(4-tert-butyl-phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]- amino}-propionic acid
37 ##STR66## 3-(5-Bromo-thiophen-2-yl)-
2(S)-{[7-(4-trans-tert-butyl- cyclohexyloxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-propionic acid 38 ##STR67##
3-(5-Bromo-4-thiophen-2-yl)- 2(S)-{[6-(4-tert-butyl- phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]- amino}-propionic acid
39 ##STR68## 2(S)-{[7-(4-trans-tert-Butyl- cyclohexyloxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-isopropenyl- thiophen-2-yl)-propionic acid 40 ##STR69##
2(S)-{[7-(4-trans-tert-Butyl- cyclohexyloxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-isopropyl-
thiophen-2-yl)-propionic acid 41 ##STR70## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-isopropyl-furan- 2-yl)-propionic acid 42 ##STR71##
2(S)-{[1-Cyclopentylmethyl- 7-(4-isopropyl-
cyclohexyloxy)-isoquinoline- 3-carbonyl]-amino}-3-(5-
isopropyl-thiophen-2-yl)- propionic acid 43 ##STR72##
2(R)-{[7-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-isopropyl-
thiophen-2-yl)-propionic acid 44 ##STR73## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-isoquinoline-3- carbonyl]-amino}-3-(5-
isopropyl-thiophen-2-yl)- propionic acid 45 ##STR74##
2(S)-{[1-Cyclopentylmethyl- 7-(4-trans-ethyl-
cyclohexyloxy)-isoquinoline- 3-carbonyl]-amino}-3-(5-
isopropyl-thiophen-2-yl)- propionic acid 46 ##STR75##
2(S)-{[1-Cyclopentylmethyl- 7-(4-isopropyl-phenoxy)-
isoquinoline-3-carbonyl]- amino}-3-(5-isopropyl-
thiophen-2-yl)-propionic acid 47 ##STR76## 2(S)-{[7-(4-tert-Butyl-
phenoxy)-1-(tetrahydro- pyran-4-yl)-isoquinoline-3-
carbonyl]-amino}-3-(5- isopropyl-thiophen-2-yl)- propionic acid 48
##STR77## 2(S)-{[6-(4-tert-Butyl- phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-isopropyl-
thiophen-2-yl)-propionic acid 49 ##STR78## 2(S)-{[7-(4-tert-Butyl-
phenyl)-1- cyclopentylmethyl- isoquinoline-3-carbonyl]-
amino}-3-(5-isopropyl- thiophen-2-yl)-propionic acid 50 ##STR79##
2(S)-{[7-(4-tert-Butyl- benzoyl)-1- cyclopentylmethyl-
isoquinoline-3-carbonyl]- amino}-3-(5-isopropyl-
thiophen-2-yl)-propionic acid 51 ##STR80##
3-(5-Acetyl-thiophen-2-yl)- 2(S)-{[7-(4-tert-butyl- phenoxy)-1-
cyclopentylmethyl- isoquinoline-3-carbonyl]- amino}-propionic acid
52 ##STR81## 7-(4-tert-Butyl-phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carboxylic acid[1-(5-isopropyl-
thiophen-2-ylmethyl)-2(R)- methanesulfonylamino-2- oxo-ethyl]-amide
53 ##STR82## 7-(4-tert-Butyl-phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carboxylic acid[1-(5-isopropyl-
thiophen-2-ylmethyl)-2(S)- methanesulfonylamino-2- oxo-ethyl]-amide
54 ##STR83## 7-(4-tert-Butyl-phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carboxylic acid[1-benzyloxycarbamoyl-
2-(5-isopropyl-thiophen-2- yl)-ethyl]-amide 55 ##STR84##
7-(4-tert-Butyl-phenoxy)-1- cyclopentylmethyl-
isoquinoline-3-carboxylic acid[1-hydroxycarbamoyl-2-
(5-isopropyl-thiophen-2-yl)- ethyl]-amide
[0208] Incomplete valences for heteroatoms such as oxygen and
nitrogen in the chemical structures listed in Table 1 are assumed
to be completed by hydrogen.
[0209] In another aspect, the present invention comprises a
pharmaceutical composition comprising the compound of Formula (I or
X) and one or more pharmaceutically acceptable carriers,
excipients, or diluents.
[0210] As used herein, the term "lower" refers to a group having
between one and six carbons.
[0211] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to ten carbon atoms,
optionally substituted with substituents selected from the group
consisting of halo, lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkyl" as used herein include, but are not limited to, methyl,
n-butyl, t-butyl, n-pentyl, isobutyl, and isopropyl, and the
like.
[0212] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group consisting of halo, lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkylene" as used herein include, but are not limited to,
methylene, ethylene, and the like.
[0213] As used herein, the term "alkenyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon double bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkenyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0214] As used herein, the term "alkenylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon double bonds,
optionally substituted with substituents selected from the group
consisting of halo, lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkenylene" group
may containing one or more O, S, S(O), or S(O).sub.2 atoms.
Examples of "alkenylene" as used herein include, but are not
limited to, ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl,
and the like.
[0215] As used herein, the term "alkynyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon triple bond, optionally substituted with substituents
selected from the group consisting of halo, lower alkyl, lower
alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, silyloxy optionally
substituted by alkoxy, alkyl, or aryl, silyl optionally substituted
by alkoxy, alkyl, or aryl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Such an "alkynyl" group may containing one or more O, S, S(O), or
S(O).sub.2 atoms.
[0216] As used herein, the term "alkynylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon triple bonds,
optionally substituted with substituents selected from the group
consisting of halo, lower alkyl, lower alkoxy, lower alkylsulfanyl,
lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto,
amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkynylene" group
may containing one or more O, S, S(O), or S(O).sub.2 atoms.
Examples of "alkynylene" as used herein include, but are not
limited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
[0217] As used herein, "cycloalkyl" refers to a alicyclic
hydrocarbon group optionally possessing one or more degrees of
unsaturation, having from three to twelve carbon atoms, optionally
substituted with substituents selected from the group consisting of
halo, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. "Cycloalkyl" includes by way
of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, or cyclooctyl, and the like.
[0218] As used herein, the term "cycloalkylene" refers to an
non-aromatic alicyclic divalent hydrocarbon radical having from
three to twelve carbon atoms and optionally possessing one or more
degrees of unsaturation, optionally substituted with substituents
selected from the group consisting of halo, lower alkyl, lower
alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. Examples of "cycloalkylene" as used herein include,
but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl,
cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl,
cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
[0219] As used herein, the term "heterocyclic" or the term
"heterocyclyl" refers to a three to twelve-membered heterocyclic
ring optionally possessing one or more degrees of unsaturation,
containing one or more heteroatomic substitutions selected from S,
SO, SO.sub.2, O, or N, optionally substituted with substituents
selected from the group consisting of halo, lower alkyl, lower
alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. Such a ring may be optionally fused to one or more
of another "heterocyclic" ring(s) or cycloalkyl ring(s). Examples
of "heterocyclic" include, but are not limited to, tetrahydrofuran,
1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,
piperazine, and the like.
[0220] As used herein, the term "heterocyclylene" refers to a three
to twelve-membered heterocyclic ring diradical optionally having
one or more degrees of unsaturation containing one or more
heteroatoms selected from S, SO, SO.sub.2, O, or N, optionally
substituted with substituents selected from the group consisting of
halo, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such a ring may be
optionally fused to one or more benzene rings or to one or more of
another "heterocyclic" rings or cycloalkyl rings. Examples of
"heterocyclylene" include, but are not limited to,
tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,
1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,
piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl,
piperazine-1,4-dyil, and the like.
[0221] As used herein, the term "aryl" refers to a benzene ring or
to an optionally substituted benzene ring system fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of halo, lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, di(lower alkyl)aminoalkyl, aminoalkyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of aryl include, but are not
limited to, phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the
like.
[0222] As used herein, the term "arylene" refers to a benzene ring
diradical or to a benzene ring system diradical fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of halo, lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, di(lower alkyl)aminoalkyl, aminoalkyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acylamino, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of "arylene" include, but are
not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the
like.
[0223] As used herein, the term "heteroaryl" refers to a five- to
seven-membered aromatic ring, or to a polycyclic heterocyclic
aromatic ring, containing one or more nitrogen, oxygen, or sulfur
heteroatoms, where N-oxides and sulfur monoxides and sulfur
dioxides are permissible heteroaromatic substitutions, optionally
substituted with substituents selected from the group consisting of
halo, lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by
alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy,
alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl,
multiple degrees of substitution being allowed. For polycyclic
aromatic ring systems, one or more of the rings may contain one or
more heteroatoms. Examples of "heteroaryl" used herein are furan,
thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,
thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,
pyridine, pyridazine, pyrazine, pyrimidine, quinoline,
isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and
indazole, and the like.
[0224] As used herein, the term "heteroarylene" refers to a five-
to seven-membered aromatic ring diradical, or to a polycyclic
heterocyclic aromatic ring diradical, containing one or more
nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur
monoxides and sulfur dioxides are permissible heteroaromatic
substitutions, optionally substituted with substituents selected
from the group consisting of halo, lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl
optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. For polycyclic aromatic ring system diradicals, one
or more of the rings may contain one or more heteroatoms. Examples
of "heteroarylene" used herein are furan-2,5-diyl,
thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,
1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,
1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,
pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the
like.
[0225] As used herein, the term "fused cycloalkylaryl" refers to a
cycloalkyl group fused to an aryl group, the two having two atoms
in common, and wherein the aryl group is the point of substitution.
Examples of "fused cycloalkylaryl" used herein include 5-indanyl,
5,6,7,8-tetrahydro-2-naphthyl, ##STR85## and the like.
[0226] As used herein, the term "fused cycloalkylarylene" refers to
a fused cycloalkylaryl, wherein the aryl group is divalent.
Examples include ##STR86## and the like.
[0227] As used herein, the term "fused arylcycloalkyl" refers to an
aryl group fused to a cycloalkyl group, the two having two atoms in
common, and wherein the cycloalkyl group is the point of
substitution. Examples of "fused arylcycloalkyl" used herein
include 1-indanyl, 2-indanyl, 1-(1,2,3,4-tetrahydronaphthyl),
##STR87## and the like.
[0228] As used herein, the term "fused arylcycloalkylene" refers to
a fused arylcycloalkyl, wherein the cycloalkyl group is divalent.
Examples include ##STR88## and the like.
[0229] As used herein, the term "fused heterocyclylaryl" refers to
a heterocyclyl group fused to an aryl group, the two having two
atoms in common, and wherein the aryl group is the point of
substitution. Examples of "fused heterocyclylaryl" used herein
include 3,4-methylenedioxy-1-phenyl, ##STR89## and the like
[0230] As used herein, the term "fused heterocyclylarylene" refers
to a fused heterocyclylaryl, wherein the aryl group is divalent.
Examples include ##STR90## and the like.
[0231] As used herein, the term "fused arylheterocyclyl" refers to
an aryl group fused to a heterocyclyl group, the two having two
atoms in common, and wherein the heterocyclyl group is the point of
substitution. Examples of "fused arylheterocyclyl" used herein
include 2-(1,3-benzodioxolyl), ##STR91## and the like.
[0232] As used herein, the term "fused arylheterocyclylene" refers
to a fused arylheterocyclyl, wherein the heterocyclyl group is
divalent. Examples include ##STR92## and the like.
[0233] As used herein, the term "fused cycloalkylheteroaryl" refers
to a cycloalkyl group fused to a heteroaryl group, the two having
two atoms in common, and wherein the heteroaryl group is the point
of substitution. Examples of "fused cycloalkylheteroaryl" used
herein include 5-aza-6-indanyl, ##STR93## and the like.
[0234] As used herein, the term "fused cycloalkylheteroarylene"
refers to a fused cycloalkylheteroaryl, wherein the heteroaryl
group is divalent. Examples include ##STR94## and the like.
[0235] As used herein, the term "fused heteroarylcycloalkyl" refers
to a heteroaryl group fused to a cycloalkyl group, the two having
two atoms in common, and wherein the cycloalkyl group is the point
of substitution. Examples of "fused heteroarylcycloalkyl" used
herein include 5-aza-1-indanyl, ##STR95## and the like.
[0236] As used herein, the term "fused heteroarylcycloalkylene"
refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl
group is divalent. Examples include ##STR96## and the like.
[0237] As used herein, the term "fused heterocyclylheteroaryl"
refers to a heterocyclyl group fused to a heteroaryl group, the two
having two atoms in common, and wherein the heteroaryl group is the
point of substitution. Examples of "fused heterocyclylheteroaryl"
used herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,
##STR97## and the like.
[0238] As used herein, the term "fused heterocyclylheteroarylene"
refers to a fused heterocyclylheteroaryl, wherein the heteroaryl
group is divalent. Examples include ##STR98## and the like.
[0239] As used herein, the term "fused heteroarylheterocyclyl"
refers to a heteroaryl group fused to a heterocyclyl group, the two
having two atoms in common, and wherein the heterocyclyl group is
the point of substitution. Examples of "fused
heteroarylheterocyclyl" used herein include
-5-aza-2,3-dihydrobenzofuran-2-yl, ##STR99## and the like.
[0240] As used herein, the term "fused heteroarylheterocyclylene"
refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl
group is divalent. Examples include ##STR100## and the like.
[0241] As used herein, the term "acid isostere" refers to a
substituent group that may ionize at physiological pH to bear a net
negative charge. Examples of such "acid isosteres" include but are
not limited to heteroaryl groups such as but not limited to
isoxazol-3-ol-5-yl, 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such
acid isosteres include but are not limited to heterocyclyl groups
such as but not limited to imidazolidine-2,4-dione-5-yl,
imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or
5-hydroxy-4H-pyran-4-on-2-yl,
1,2,5-thiadiazolidin-3-one-1,1-dioxide-4-yl, or
1,2-5-thiadiazolidin-3-one-1,1-dioxide-5-yl.
[0242] As used herein, the term "ester isostere" refers to a
substituent group that can be metabolically stable and can retain
the selectivity and affinity of a corresponding ester toward a
target protein. Examples of such "ester isosteres" include, but are
not limited to, heteroaryl groups such as, but not limited to,
1,3-oxazole-5-yl, 1,3-oxazole-2-yl, 1,2,3-oxadiazole-5-yl,
1,2,4-oxadiazole-5-yl, 1,3,4-oxadiazole-5-yl,
1,2,3-thiadiazole-5-yl, 1,2,4-thiadiazole-5-yl,
1,3,4-thiadiazole-5-yl, 5-alkyl-1,3-oxazole-2-yl,
2-alkyl-1,3-oxazole-5-yl, 4-alkyl-1,2,3-oxadiazole-5-yl,
3-alkyl-1,2,4-oxadiazole-5-yl, 2-alkyl-1,3,4-oxadiazole-5-yl,
4-alkyl-1,2,3-thiadiazole-5-yl, 3-alkyl-1,2,4-thiadiazole-5-yl,
2-alkyl-1,3,4-thiadiazole-5-yl, 1,2,4-triazole-1-yl,
3-alkyl-1,2,4-triazole-1-yl, tetrazole-1-yl, and
1-alkyl-tetrazole-5-yl; aryl groups such as, but not limited to,
3,5-difluoro-4-alkoxyphenyl; and heterocyclyl groups such as, but
not limited to, 1-alkyl-imidazolidine-2,4-dione-5-yl,
imidazolidine-2,4-dione-1-yl,
3-alkyl-1,3-thiazolidine-2,4-dione-5-yl, and
5-alkoxy-4H-pyran-4-on-2-yl. The alkyl groups in the heterocyclyl,
aryl, and heteroaryl groups of the ester isosteres may be replaced
with a phenyl or alkylphenyl group.
[0243] As used herein, the term "direct bond", where part of a
structural variable specification, refers to the direct joining of
the substituents flanking (preceding and succeeding) the variable
taken as a "direct bond".
[0244] As used herein, the term "alkoxy" refers to the group
R.sub.aO--, where R.sub.a is alkyl.
[0245] As used herein, the term "alkenyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkenyl.
[0246] As used herein, the term "alkynyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkynyl.
[0247] As used herein, the term "alkylsulfanyl" refers to the group
R.sub.aS--, where R.sub.a is alkyl.
[0248] As used herein, the term "alkenylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is alkenyl.
[0249] As used herein, the term "alkynylsulfanyl" refers to the
group R.sub.aS--, where R.sub.a is alkynyl.
[0250] As used herein, the term "alkylsulfenyl" refers to the group
R.sub.aS(O)--, where R.sub.a is alkyl.
[0251] As used herein, the term "alkenylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkenyl.
[0252] As used herein, the term "alkynylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkynyl.
[0253] As used herein, the term "alkylsulfonyl" refers to the group
R.sub.aSO.sub.2--, where R.sub.a is alkyl.
[0254] As used herein, the term "alkenylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.a is alkenyl.
[0255] As used herein, the term "alkynylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.a is alkynyl.
[0256] As used herein, the term "acyl" refers to the group
R.sub.aC(O)--, where R.sub.a is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0257] As used herein, the term "aroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is aryl.
[0258] As used herein, the term "heteroaroyl" refers to the group
R.sub.aC(O)--, where R.sub.a is heteroaryl.
[0259] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.a is alkyl.
[0260] As used herein, the term "acyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0261] As used herein, the term "aroyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aryl.
[0262] As used herein, the term "heteroaroyloxy" refers to the
group R.sub.aC(O)O--, where R.sub.a is heteroaryl.
[0263] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s) which occur and events that do not occur.
[0264] As used herein, the term "substituted" refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0265] As used herein, the terms "contain" or "containing" can
refer to in-line substitutions at any position along the above
defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one
or more of any of O, S, SO, SO.sub.2, N, or N-alkyl, including, for
example, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--SO.sub.2--CH.sub.2--, --CH.sub.2--NH--CH.sub.3 and so
forth.
[0266] As used herein, the term "solvate" is a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
Formula (X or XI)) and a solvent. Such solvents for the purpose of
the invention may not substantially interfere with the biological
activity of the solute. Solvents may be, by way of example, water,
ethanol, or acetic acid.
[0267] As used herein, the term "biohydrolyzable ester" is an ester
of a drug substance (in this invention, a compound of Formula (X or
XI)) which either a) does not interfere with the biological
activity of the parent substance but confers on that substance
advantageous properties in vivo such as duration of action, onset
of action, and the like, or b) is biologically inactive but is
readily converted in vivo by the subject to the biologically active
principle. The advantage is that, for example, the biohydrolyzable
ester is orally absorbed from the gut and is transformed to Formula
(I or X) in plasma. Many examples of such are known in the art and
include by way of example lower alkyl esters (e.g.,
C.sub.1-C.sub.4), lower acyloxyalkyl esters, lower
alkoxyacyloxyalkyl esters, alkoxyacyloxy esters, alkyl acylamino
alkyl esters, and choline esters.
[0268] As used herein, the term "biohydrolyzable amide" is an amide
of a drug substance (in this invention, a compound of general
formula (I or X)) which either a) does not interfere with the
biological activity of the parent substance but confers on that
substance advantageous properties in vivo such as duration of
action, onset of action, and the like, or b) is biologically
inactive but is readily converted in vivo by the subject to the
biologically active principle. The advantage is that, for example,
the biohydrolyzable amide is orally absorbed from the gut and is
transformed to Formula (I or X) in plasma. Many examples of such
are known in the art and include by way of example lower alkyl
amides, alpha-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides.
[0269] As used herein, the term "prodrug" includes biohydrolyzable
amides and biohydrolyzable esters and encompasses a) compounds in
which the biohydrolyzable functionality in such a prodrug is
encompassed in the compound of formula (I or X), and b) compounds
which may be oxidized or reduced biologically at a given functional
group to yield drug substances of formula (I or X). Examples of
these functional groups include, but are not limited to,
1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,
1,4-cyclohexadiene, tert-butyl, and the like.
[0270] Whenever the terms "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g.
arylalkoxyaryloxy) they shall be interpreted as including those
limitations given above for "alkyl" and "aryl". Designated numbers
of carbon atoms (e.g. C.sub.1-10) shall refer independently to the
number of carbon atoms in an alkyl, alkenyl or alkynyl or cyclic
alkyl moiety or to the alkyl portion of a larger substituent in
which the term "alkyl" appears as its prefix root.
[0271] As used herein, the term "oxo" shall refer to the
substituent .dbd.O.
[0272] As used herein, the term "halogen" or "halo" shall include
iodine, bromine, chlorine and fluorine.
[0273] As used herein, the term "mercapto" shall refer to the
substituent --SH.
[0274] As used herein, the term "carboxy" shall refer to the
substituent --COOH.
[0275] As used herein, the term "cyano" shall refer to the
substituent --CN.
[0276] As used herein, the term "aminosulfonyl" shall refer to the
substituent --SO.sub.2NH.sub.2.
[0277] As used herein, the term "carbamoyl" shall refer to the
substituent --C(O)NH.sub.2.
[0278] As used herein, the term "sulfanyl" shall refer to the
substituent --S--.
[0279] As used herein, the term "sulfenyl" shall refer to the
substituent --S(O)--.
[0280] As used herein, the term "sulfonyl" shall refer to the
substituent --S(O).sub.2--.
[0281] The compounds can be prepared according to the following
reaction Schemes (in which variables are as defined before or are
defined) using readily available starting materials, reagents and
conventional synthesis procedures. In these reactions, it is also
possible to make use of variants which are themselves known to
those of ordinary skill in this art, but are not mentioned in
greater detail.
[0282] The present invention also provides a method for the
synthesis of compounds useful as intermediates in the preparation
of compounds of Formula (I or X) along with methods for the
preparation of compounds of Formula (I or X).
[0283] Scheme XIV describes the synthesis of a compound of formula
(66). R.sub.85 and R.sub.86 may be groups such as but not limited
to hydrogen, alkyl, or -alkylene-aryl. R.sub.81 may be a group such
as the side chain of a natural or unnatural amino acid. R.sub.82
may be a group such as aryl, heteroaryl, alkyl, or cycloalkyl.
R.sub.84 may be a group such as but not limited to alkyl, aryl,
heteroaryl, cycloalkyl, -alkylene-cycloalkyl, or
-alkylene-aryl.
[0284] Compound (62) represents a nitrogen containing fused
heterocyclylaryl ring system which may be synthesized by methods
known in the art, such as acid catalyzed condensation of the
corresponding amino acid with a carbonyl compound
R.sub.85C(O)R.sub.86, followed by protection at nitrogen with a
protecting group such as but not limited to BOC. (62) may be
treated with a peptide coupling agent such as DIC or HBTU, in the
presence or absence of a base such as DIEA, in a solvent such as
DMF of DCM, and an amino ester such as (63), to provide (64). An
amine similar in structure to (63) may also be used to provide (64)
without a methoxycarbonyl functionality. The phenol functionality
of (64) may be functionalized by treatment of (64) with a primary
or secondary alcohol in a solvent such as THF, with dialkyl
azodicarboxylate and triphenylphosphine at a temperature of from
-20.degree. C. to 25.degree. C., to give (65) where R.sub.82 is
alkyl, substituted alkyl, or cycloalkyl. (64) may also be treated
with a aryl or heteroaryl boronic acid and copper (II) acetate to
afford (65) where R.sub.82 is aryl or heteroaryl. The PG.sub.1
group of (65) may be removed as appropriate; the nitrogen thus
freed may be functionalized with R.sub.83, where R.sub.83
represents groups such as but not limited to a alkylsulfenyl group,
a alkoxycarbonyl group, or an acyl or alkanoyl group. The methyl
ester of the intermediate may be removed by treatment with, for
example, lithium hydroxide in aqueous THF--methanol at a
temperature of from 0.degree. C. to 25.degree. C., to afford (66).
##STR101##
[0285] Scheme XV depicts the synthesis of a compound of formula
(70). R.sub.85, R.sub.82, and R.sub.81 have the meanings described
for Scheme XIV. The phenolic functionality of (67) may be
functionalized as in Scheme XIV, and the PG.sub.1 protecting group
may be removed with a reagent such as TFA, where PG.sub.1 is tBOC.
(68) may be treated with a reagent such as dichlorodicyanoquinone
(DDQ) in a solvent such as toluene, at a temperature of from
25.degree. C. to 110.degree. C., to afford the acid (69) after
hydrolysis of the ester with a reagent such as lithium hydroxide in
a solvent such as aqueous THF. In manner similar to that described
in Scheme XIV, the acid (69) may be coupled with an amino ester or
other amine and the ester, if present, may be hydrolyzed with
aqueous alkali to afford (70). ##STR102##
[0286] Scheme XVI describes the synthesis of intermediates and
further compounds of Formula I. The acid (69) may be coupled with a
functionalized bromoaryl alanine ester, or other similar
bromoaromatic substituted amine, under conditions described
previously to afford (71). (71) may be transformed to (72)
employing conditions described in Scheme II. Similarly, (69) may be
coupled with a hydroxyaryl alanine ester, or other similar
hydroxyaryl or hydroxyheteroaryl substituted amine, to give (73),
which may be functionalized as described in Scheme III to provide
(74). ##STR103##
[0287] Scheme XVII describes synthesis of compounds of formula
(79). R.sub.85, R.sub.82, and R.sub.81 have the meanings as
described for Scheme XIV. PG.sub.2 represents a hydroxyl protecting
group. An N-acylated amino acid ester (75) may be treated with a
reagent such as oxalyl chloride in a solvent such as DCM, at a
temperature of from 0.degree. C. to 25.degree. C., to afford a
imidoyl chloride intermediate, which is treated with a reagent such
as but not limited to FeCl.sub.3 in DCM, followed by treatment with
sulfuric acid in methanol to afford the cyclized product;
concomitant removal of PG.sub.2 (where PG.sub.2 is tert-butyl or
benzyl) may occur, to afford (76). Where PG.sub.2 is not removed
during these above steps, it may be removed, where PG.sub.2 is
tert-butyl, by treatment with TFA or HCl in dioxane. (76) may be
dehydrogenated by treatment with Pd/C in xylene at a temperature of
from 25.degree. C. to 130.degree. C., or by treatment with copper
(II) acetate in DCM, to afford (77). The phenolic function of (77)
may be functionalized as for Scheme XIV; as well, the product (78)
after ester hydrolysis may be coupled with an amine or amino acid
ester to give, after hydrolysis, the acid (79). ##STR104##
[0288] The term "amino-protecting group" as used herein refers to
substituents of the amino group commonly employed to block or
protect the amino functionality while reacting other functional
groups on the compound. Examples of such amino-protecting groups
include the formyl group, the trityl group, the phthalimido group,
the trichloroacetyl group, the chloroacetyl, bromoacetyl and
iodoacetyl groups, urethane-type blocking groups such as
benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,
1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)prop-2-yloxycarbonyl,
cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)ethoxycarbonyl,
2(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl
("FMOC"), t-butoxycarbonyl ("BOC"),
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the
benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the
diphenylphosphine oxide group and like amino-protecting groups. The
species of amino-protecting group employed is not critical so long
as the derivatized amino group is stable to the condition of
subsequent reaction(s) on other positions of the compound of
Formula (I or X) and can be removed at the desired point without
disrupting the remainder of the molecule. Commonly used
amino-protecting groups are the allyloxycarbonyl, the
t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl
groups. Similar amino-protecting groups used in the cephalosporin,
penicillin and peptide art are also embraced by the above terms.
The related term "protected amino" or "protected amino group"
defines an amino group substituted with an amino-protecting group
discussed above.
[0289] The term "hydroxyl protecting group" as used herein refers
to substituents of the alcohol group commonly employed to block or
protect the alcohol functionality while reacting other functional
groups on the compound. Examples of such alcohol -protecting groups
include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the
trityl group, the trichloroacetyl group, urethane-type blocking
groups such as benzyloxycarbonyl, and the trialkylsilyl group,
examples of such being trimethylsilyl, tert-butyldimethylsilyl,
phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The
choice of alcohol-protecting group employed is not critical so long
as the derivatized alcohol group is stable to the condition of
subsequent reaction(s) on other positions of the compound of the
formulae and can be removed at the desired point without disrupting
the remainder of the molecule. The related term "protected
hydroxyl" or "protected alcohol" defines a hydroxyl group
substituted with a hydroxyl-protecting group as discussed
above.
[0290] The term "carboxyl protecting group" as used herein refers
to substituents of the carboxyl group commonly employed to block or
protect the --OH functionality while reacting other functional
groups on the compound. Examples of such alcohol -protecting groups
include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the
trityl group, the allyl group, the trimethylsilylethoxymethyl
group, the 2,2,2-trichloroethyl group, the benzyl group, and the
trialkylsilyl group, examples of such being trimethylsilyl,
tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and
thexyldimethylsilyl. The choice of carboxyl protecting group
employed is not critical so long as the derivatized alcohol group
is stable to the condition of subsequent reaction(s) on other
positions of the compound of the formulae and can be removed at the
desired point without disrupting the remainder of the molecule. The
related term "protected carboxyl" defines a carboxyl group
substituted with a carboxyl-protecting group as discussed
above.
[0291] Further examples of progroups referred to by the above terms
are described by J. W. Barton, "Protective Groups In Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, and T. W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981.
[0292] The invention further provides pharmaceutical compositions
comprising the factor XI or dual Factor IX/XI modulating compounds
of the invention. The term "pharmaceutical composition" is used
herein to denote a composition that may be administered to a
mammalian host, e.g., orally, topically, parenterally, by
inhalation spray, or rectally, in unit dosage formulations
containing conventional non-toxic carriers, diluents, adjuvants,
vehicles and the like. The term "parenteral" as used herein,
includes subcutaneous injections, intravenous, intramuscular,
intracisternal injection, or by infusion techniques.
[0293] The term "factor IX" is used herein to refer to blood
coagulation factor IX, including both activated and non-activated
forms thereof.
[0294] The term "therapeutically effective amount" is used herein
to denote that amount of a drug or pharmaceutical agent that will
elicit the therapeutic response of an animal or human that is being
sought.
[0295] The pharmaceutical compositions containing a compound of the
invention may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous, or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any known method, and such compositions may
contain one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents, and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient
in admixture with non-toxic pharmaceutically-acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the techniques described in
U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, to form osmotic
therapeutic tablets for controlled release.
[0296] Formulations for oral use may also be presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or a soft gelatin capsules wherein the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0297] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more coloring agents, one or more flavoring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[0298] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0299] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavoring, and coloring agents may also be present.
[0300] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example a liquid paraffin, or a mixture thereof. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
[0301] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[0302] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the invention. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will thus melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene glycols, for example.
[0303] For topical use, creams, ointments, jellies, solutions of
suspensions, etc., containing the compounds of the invention are
contemplated. For the purpose of this application, topical
applications shall include mouth washes and gargles. The compounds
of the present invention may also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles, and multilamellar vesicles. Liposomes
may be formed from a variety of phospholipids, such as cholesterol,
stearylamine, or phosphatidylcholines. Also provided by the present
invention are prodrugs of the invention.
[0304] Pharmaceutically-acceptable salts of the compounds of the
present invention, where a basic or acidic group is present in the
structure, are also included within the scope of the invention. The
term "pharmaceutically acceptable salts" refers to non-toxic salts
of the compounds of this invention which are generally prepared by
reacting the free base with a suitable organic or inorganic acid or
by reacting the acid with a suitable organic or inorganic base.
Representative salts include the following salts: Acetate,
Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,
Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,
Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate,
Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate,
Methanesulfonate, Methylbromide, Methylnitrate, Methylsulfate,
Monopotassium Maleate, Mucate, Napsylate, Nitrate,
N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate,
Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium,
Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate,
Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and
Valerate. When an acidic substituent is present, such as --COOH,
there can be formed the ammonium, morpholinium, sodium, potassium,
barium, calcium salt, and the like, for use as the dosage form.
When a basic group is present, such as amino or a basic heteroaryl
radical, such as pyridyl, an acidic salt, such as hydrochloride,
hydrobromide, phosphate, sulfate, trifluoroacetate,
trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,
succinate, citrate, tartrate, fumarate, mandelate, benzoate,
cinnamate, methanesulfonate, ethanesulfonate, picrate and the like,
and include acids related to the pharmaceutically-acceptable salts
listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p.
1-19.
[0305] Other salts which are not pharmaceutically acceptable may be
useful in the preparation of compounds of the invention and these
form a further aspect of the invention.
[0306] In addition, some of the compounds of Formula (I or X) may
form solvates with water or common organic solvents. Such solvates
are also encompassed within the scope of the invention.
[0307] Thus, in another aspect of the present invention, there is
provided a pharmaceutical composition comprising a therapeutically
effective amount of a compound of Formula (I or X), or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, and
one or more pharmaceutically acceptable carriers, excipients, or
diluents. In an embodiment of the pharmaceutical composition, the
compound of Formula (I or X) is an antagonist of factor XI or an
antagonist of factor IX/XI activity. In another embodiment of the
pharmaceutical composition, the compound of Formula (I or X) is a
partial antagonist of factor XI activity or of both factor XI/IX
activity, wherein a partial antagonist comprises a compound that
inhibits less than complete activity at a physiologically tolerable
dose. In another embodiment of the pharmaceutical composition, the
compound of Formula (I or X) is a partial antagonist of factor XI
activity or of factor IX/XI activity, wherein the compound of
Formula (I or X) inhibits up to 95% of factor IX or factor IX/XI
activity. In another embodiment of the pharmaceutical composition,
the compound of Formula (I or X) is a partial antagonist of factor
XI activity or of factor IX/XI activity, wherein the compound of
Formula (I or X) inhibits up to 80% of factor XI or factor IX/XI
activity. In another embodiment of the pharmaceutical composition,
the compound of Formula (I or X) is a partial antagonist of factor
XI activity or of factor IX/XI activity, wherein the compound of
Formula (I or X) inhibits up to 50% of factor XI or IX/XI activity.
In another embodiment of the pharmaceutical composition, the
compound of Formula (I or X) antagonizes blood clotting mediated by
factor XI or IX/XI.
[0308] In another aspect of the present invention, there is
provided a pharmaceutical composition comprising a therapeutically
effective amount of a compound of Formula (I or X), or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, and
one or more pharmaceutically acceptable carriers, excipients, or
diluents, wherein said therapeutically effective amount of Formula
(I or X) preferentially inhibits the intrinsic clotting cascade as
compared to the extrinsic clotting cascade. In an embodiment of the
pharmaceutical composition, said therapeutically effective amount
of Formula (I or X) inhibits the intrinsic clotting cascade by
greater than 80% and inhibits the extrinsic clotting cascade by
less than 50%. In another embodiment of the pharmaceutical
composition, said therapeutically effective amount of Formula (I or
X) comprises an amount sufficient to achieve and maintain a
sustained blood level that at least partially antagonizes factor XI
or factor IX/XI biological activity. In another embodiment, said
sustained blood level comprises a concentration ranging from about
0.01 .mu.M to 2 mM. In another embodiment, said sustained blood
level comprises a concentration ranging from about 0.05 .mu.M to
100 .mu.M. In another embodiment, said sustained blood level
comprises a concentration ranging from about 0.1 .mu.M to about 30
.mu.M.
[0309] In another aspect of the present invention, there is
provided a pharmaceutical composition comprising a therapeutically
effective amount of a compound of Formula (I or X), or a
pharmaceutically acceptable salt, solvate, or prodrug thereof, and
one or more pharmaceutically acceptable carriers, excipients, or
diluents, wherein said therapeutically effective amount comprises a
sufficient amount of the compound of Formula (I or X) to at least
partially inhibit the biological activity of factor XI or factor
IX/XI in a subject, a sufficient amount of the compound of Formula
(I or X) for at least partial amelioration of at least one factor
XI- or factor IX/XI-mediated disease, or a sufficient amount of the
compound of Formula (I or X) to at least partially inhibit the
intrinsic clotting cascade in a subject. In an embodiment of the
pharmaceutical composition, said factor XI- or factor
IX/XI-mediated disease comprises stroke. In another embodiment of
the pharmaceutical composition, said factor XI- or factor
IX/XI-mediated disease comprises deep vein thrombosis. In another
embodiment of the pharmaceutical composition, said factor XI- or
factor IX/XI-mediated disease comprises deep vein thrombosis,
wherein said thrombosis is associated with surgical procedures,
long periods of confinement, acquired or inherited pro-coagulant
states including anti-phospholipid antibody syndrome, protein C
deficiency and protein S deficiency, or acute and chronic
inflammation including recurrent miscarriage or Systemic Lupus
Erythmatosis (SLE). In another embodiment, said factor XI- or
factor IX/XI-mediated disease comprises excessive clotting
associated with the treatment of kidney diseases by hemodialysis
and/or venous hemofiltration. In another embodiment, said factor
XI- or factor IX/XI-mediated disease comprises cardiovascular
disease. In another embodiment, said factor XI- or factor
IX/XI-mediated disease comprises cardiovascular disease, wherein
said cardiovascular disease comprises myocardial infarction,
arrhythmia, or aneurysm.
[0310] In another aspect, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of the compound of Formula (I or X), and one or more
pharmaceutically acceptable carriers, excipients, or diluents,
wherein said pharmaceutical composition is used to replace or
supplement compounds that reduce clotting.
[0311] In another aspect, the present invention provides a
pharmaceutical composition comprising a therapeutically effective
amount of the compound of Formula (I or X), and one or more
pharmaceutically acceptable carriers, excipients, or diluents,
further comprising one or more therapeutic agents.
[0312] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor XI
or factor IX/XI comprising administering to a subject in need
thereof a compound of Formula (I or X). In embodiment of the
method, said compound of Formula (I or X) is an antagonist of
factor XI or factor IX/XI activity. In another embodiment of the
method, said compound of Formula (I or X) antagonizes blood
clotting mediated by factor XI or factor IX/XI. In another
embodiment of the method, said compound of Formula (I or X) is
administered in an amount sufficient to partially antagonize the
biological activity of factor XI or factor IX/XI in said subject.
In another embodiment of the method, said compound of Formula (I or
X) is an antagonist of factor XI or factor IX/XI activity. In
another embodiment of the method, said compound of Formula (I or X)
antagonizes blood clotting mediated by factor XI or factor IX/XI.
In another embodiment of the method, said compound of Formula (I or
X) is administered in an amount sufficient to partially antagonize
the biological activity of factor XI or factor IX/XI in said
subject. In another embodiment of the method, said pharmaceutical
composition is administered in the form of an oral dosage or
parenteral dosage unit. In another embodiment of the method, said
compound of Formula (I or X) is administered as a dose in a range
from about 0.01 to 1,000 mg/kg of body weight per day. In another
embodiment of the method, said compound of Formula (I or X) is
administered as a dose in a range from about 0.1 to 100 mg/kg of
body weight per day. In another embodiment of the method, said
compound of Formula (I or X) is administered as a dose in a range
from about 0.5 to 10 mg/kg of body weight per day. In another
embodiment, said compound of Formula (I or X) is used to replace or
supplement compounds that reduce clotting.
[0313] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor XI
or factor IX/XI comprising administering to a subject in need
thereof a compound of Formula (I or X), wherein said compound of
Formula (I or X) is administered to said subject as a
pharmaceutical composition comprising a therapeutically effective
amount of said compound of Formula (I or X) and one or more
pharmaceutically acceptable carriers, excipients, or diluents. In
an embodiment of the method, said therapeutically effective amount
of the compound of Formula (I or X) comprises a sufficient amount
of the compound of Formula (I or X) to at least partially inhibit
the intrinsic clotting cascade in said subject. In another
embodiment of the method, said therapeutically effective amount of
Formula (I or X) preferentially inhibits the intrinsic clotting
cascade as compared to the extrinsic clotting cascade. In another
embodiment of the method, said therapeutically effective amount of
Formula (I or X) inhibits the intrinsic clotting cascade by greater
than 80% and inhibits the extrinsic clotting cascade by less than
50%. In another embodiment of the method, said therapeutically
effective amount of the compound of Formula (I or X) comprises an
amount sufficient to achieve and maintain a sustained blood level
that at least partially antagonizes factor XI or factor IX/XI
biological activity. In another embodiment, said sustained blood
level comprises a concentration ranging from about 0.01 .mu.M to 2
mM. In another embodiment, said sustained blood level comprises a
concentration ranging from about 0.05 .mu.M to 100 .mu.M In another
embodiment, said sustained blood level comprises a concentration
ranging from about 0.1 .mu.M to about 30 .mu.M. In another
embodiment of the method, said pharmaceutical composition further
comprises one or more therapeutic agents.
[0314] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor XI
or factor IX/XI comprising administering to a subject in need
thereof a compound of Formula (I or X), wherein said compound of
Formula (I or X) is a partial antagonist of factor XI or factor
IX/XI, wherein a partial antagonist comprises a compound that
inhibits less than complete activity at a physiologically tolerable
dose. In an embodiment of the method, said compound of Formula (I
or X) inhibits up to 95% of factor XI or factor IX/XI activity. In
another embodiment of the method, said compound of Formula (I or X)
inhibits up to 80% of factor XI or factor IX/XI activity. In
another embodiment of the method, said compound of Formula (I or X)
inhibits up to 50% of factor XI or factor IX/XI activity.
[0315] In another aspect, the present invention provides a method
for the inhibition of the normal biological function of factor XI
or factor IX/XI comprising administering to a subject in need
thereof a compound of Formula (I or X), wherein said compound of
Formula (I or X) is administered to said subject as a
pharmaceutical composition comprising a therapeutically effective
amount of said compound of Formula (I or X) and one or more
pharmaceutically acceptable carriers, excipients, or diluents,
wherein said therapeutically effective amount of the compound of
Formula (I or X) comprises a sufficient amount of the compound of
Formula (I or X) for treatment or prevention of factor XI- or
factor IX/XI-mediated diseases. In an embodiment of the method,
said factor XI- or factor IX/XI-mediated disease comprises stroke.
In another embodiment of the method, said factor XI- or factor
IX/XI-mediated disease comprises deep vein thrombosis. The
thrombosis may be associated with surgical procedures, long periods
of confinement, acquired or inherited pro-coagulant states
including anti-phospholipid antibody syndrome, protein C deficiency
and protein S deficiency, or acute and chronic inflammation
including recurrent miscarriage or Systemic Lupus Erythmatosis
(SLE). In another embodiment of the method, said factor XI- or
factor IX/XI-mediated disease comprises clotting associated with
the treatment of kidney disease by hemodialysis and/or venous
hemofiltration. In another embodiment of the method, said factor
XI- or factor IX/XI-mediated disease comprises cardiovascular
disease. The cardiovascular disease may be associated myocardial
infarction, arrhythmia, or aneurysm.
[0316] In a further aspect of the present invention, the factor XI
or dual factor IX/XI modulators of the invention are utilized in
adjuvant therapeutic or combination therapeutic treatments with
other known therapeutic agents.
[0317] The term "treatment" as used herein, refers to the full
spectrum of treatments for a given disorder from which the patient
is suffering, including alleviation of one, most of all symptoms
resulting from that disorder, to an outright cure for the
particular disorder or prevention of the onset of the disorder.
[0318] The following is a non-exhaustive listing of adjuvants and
additional therapeutic agents which may be utilized in combination
with the factor Ixa antagonists of the present invention: [0319] 1.
Analgesics: Aspirin [0320] 2. NSAIDs (Nonsteroidal
anti-inflammatory drugs): Ibuprofen, Naproxen, Diclofenac [0321] 3.
DMARDs (Disease-Modifying Antirheumatic drugs): Methotrexate, gold
preparations, hydroxychloroquine, sulfasalazine [0322] 4. Biologic
Response Modifiers, DMARDs: Etanercept, Infliximab
Glucocorticoids
[0323] In another embodiment, the present invention provides a
method of treating or preventing a factor IXa mediated diseases,
the method comprising administering to a subject in need thereof, a
therapeutically effective amount of a compound of Formula (I or X)
alone or in combination with therapeutic agents selected from the
group consisting of antibiotics, hormones, biologic response
modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids,
thrombolytic agents, antidepressants, and anticonvulsants.
[0324] The compound of Formula (I or X) of the present invention,
may be administered at a dosage level of from about 0.01 to 1000
mg/kg of the body weight of the subject being treated. In another
embodiment, The compound of Formula (I or X) of the present
invention, may be administered at a dosage range between 0.01 and
100 mg/kg In another embodiment, the compound of Formula (I or X)
of the present invention, may be administered at a dosage range
between 0.5 to 10 mg/kg of body weight per day. The amount of
active ingredient that may be combined with the carrier materials
to produce a single dosage will vary depending upon the host
treated and the particular mode of administration. For example, a
formulation intended for oral administration to humans may contain
1 mg to 2 grams of a compound of Formula (I or X) with an
appropriate and convenient amount of carrier material which may
vary from about 5 to 95 percent of the total composition. Dosage
unit forms will generally contain between from about 5 mg to about
500 mg of active ingredient. This dosage may be individualized by
the clinician based on the specific clinical condition of the
subject being treated. Thus, it will be understood that the
specific dosage level for any particular patient will depend upon a
variety of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0325] The general procedures used in the methods of the present
invention are described below.
[0326] Common names and definitions for resin reagents used in the
disclosure are; TABLE-US-00002 Merrifield p-Chloromethyl
polystyrene Hydroxy-Merrifield p-Hydroxymethyl polystyrene Wang
(4-Hydroxymethyl)phenoxymethyl polystyrene Wang carbonate
4-(p-nitrophenyl carbonate) phenoxymethyl polystyrene Rink Resin
4-(2',4'-Dimethoxyphenyl-Fmco-aminomethyl)- phenoxy polystyrene
resin Wang Bromo Resin (4-Bromomethyl)phenoxymethyl polystyrene THP
Resin 3,4-Dihydro-2H-pyran-2-ylmethoxymethyl polystyrene
Aldehyde resin can refer to the following: [0327]
4-Benzyloxybenzaldehyde polystyrene [0328] 3-Benzyloxybenzaldehyde
polystyrene [0329] 4-(4-Formyl-3-methoxyphenoxy)butyryl-aminomethyl
polystyrene [0330] 2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene
[0331] 2-(3,5-dimethoxy-4-formylphenoxy)ethoxy-methyl polystyrene
[0332] 2-(3,5-dimethoxy-4-formylphenoxy)ethoxy polystyrene [0333]
(3-Formylindolyl)acetamidomethyl polystyrene [0334]
(4-Formyl-3-methoxyphenoxy) grafted
(polyethyleneglycol)-polystyrene; or [0335]
(4-Formyl-3-methoxyphenoxy)methylpolystyrene. Abbreviations used in
the Examples are as follows: APCI=atmospheric pressure chemical
ionization BOC=tert-butoxycarbonyl
BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium
hexafluorophosphate d=day DIAD=diisopropyl azodicarboxylate
DCC=dicyclohexylcarbodiimide DCE=1,2-dichloroethane
DCM=dichloromethane DIC=diisopropylcarbodiimide
DIEA=diisopropylethylamine DMA=N,N-dimethylacetamide
DMAP=dimethylaminopyridine DME=1,2 dimethoxyethane
DMF=N,N-dimethylformamide DMPU=1,3-dimethypropylene urea
DMSO=dimethylsulfoxide
EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
EDTA=ethylenediamine tetraacetic acid ELISA=enzyme-linked
immunosorbent assay ESI=electrospray ionization ether=diethyl ether
EtOAc=ethyl acetate FBS=fetal bovine serum g=gram h=hour
HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate HMPA=hexamethylphosphoric triamide
HOBt=1-hydroxybenzotriazole Hz=hertz i.v.=intravenous kD=kiloDalton
L=liter LAH=lithium aluminum hydride LDA=lithium diisopropylamide
LPS=lipopolysaccharide M=molar m/z=mass to charge ratio
mbar=millibar MeOH=methanol mg=milligram min=minute mL=milliliter
mM=millimolar mmol=millimole mol=mole mp=melting point MS=mass
spectrometry N=normal NMM=N-methylmorpholine, 4-methylmorpholine
NMR=nuclear magnetic resonance spectroscopy p.o.=per oral
PBS=phosphate buffered saline solution PMA=phorbol myristate
acetate ppm=parts per million psi=pounds per square inch
R.sub.f=relative TLC mobility rt=room temperature s.c.=subcutaneous
SPA=scintillation proximity assay TEA=triethylamine
TFA=trifluoroacetic acid THF=tetrahydrofuran THP=tetrahydropyranyl
TLC=thin layer chromatography TMSBr=bromotrimethylsilane,
trimethylsilylbromide T.sub.r=retention time General Procedure
A
[0336] To a solution of a carboxylic acid (1.0 mmol) in DMF was
added an amino acid methyl ester (1.2 mmol), HBTU (1.1 mmol), and
DIEA (4.0 mmol) and the mixture was stirred overnight. After
completion of the reaction, sufficient amount of water was added
and the mixture was extracted with ethyl acetate. The organic layer
washed with water, brine, dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure to afford the amide. The crude
product was purified by flash chromatography (silica,
Hexanes:EtOAc) to afford the pure product.
General Procedure B
[0337] To a mixture of phenol (1 mmol) and aryl or heteroaryl
fluoride (2 mmol) in DMF was added solid potassium carbonate (5
mmol), and the mixture was heated at 80.degree. C. for 12 h. After
completion of the reaction, sufficient amount of water was added,
and the mixture was extracted with ethyl acetate. The organic layer
washed with water, brine, dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure to obtain crude product. The
crude material obtained was purified by flash chromatography
(silica, Hexanes:EtOAc) to afford the desired ether.
General Procedure C
[0338] To a solution of ester in THF--CH.sub.3OH (4:1), 2 N lithium
hydroxide solution (5 eq) was added, and the resulting reaction
mixture was stirred at 0.degree. C. for 30 minutes and then warmed
to rt. After completion of the reaction the mixture was acidified
with 2N HCl, extracted with ethyl acetate, the organic layer washed
with brine, dried over (Na.sub.2SO.sub.4), and the solvent was
removed under reduced pressure to afford the product.
General Procedure D
[0339] To a solution of an aryl bromide or heteroaryl bromide (1
mmol) in DME or toluene were added a boronic acid (2 eq),
Pd(PPh.sub.3).sub.4 (ca. 10 mol %), 2N Na.sub.2CO.sub.3 solution (3
mmol). The mixture was heated at 75.degree. C. for 12 h. After
completion of the reaction, solvent was evaporated under reduced
pressure and the residue was purified by column chromatography to
provide the desired ester. The resulting ester was hydrolyzed as
described in procedure C yielding the acid.
General Procedure E
[0340] To a solution of an aniline or amine (1.0 mmol) in DCE (10
mL) was added an aldehyde (2.0-2.2 mmol), acetic acid (3.0 mmol)
and sodium triacetoxyborohydride (2.5 mmol) or sodium
cyanoborohydride and the mixture was stirred overnight. After
completion of the reaction, 50 mL of DCM was added and the organic
layer washed with saturated sodium bicarbonate solution and brine,
and then dried over Na.sub.2SO.sub.4. The solvent was removed in
vacuum to afford the product, which was purified by flash
chromatography.
General Procedure F
[0341] To a solution of an aniline or amine (1.0 mmol) in DCM (10
mL) was added a sulfonyl chloride (1.0 mmol), pyridine (10.0 mmol),
and the mixture was stirred overnight. After completion of the
reaction, 50 mL of DCM was added and the organic layer washed with
1N HCl, saturated sodium bicarbonate solution, and brine, and then
dried over Na.sub.2SO.sub.4. The solvent was removed in vacuum to
afford the sulfonamide, which was purified by flash
chromatography.
General Procedure G
[0342] A flask was charged with phenol or aniline (1.0 equiv),
Cu(OAc).sub.2 (1.0 equiv), arylboronic acid (1.0-3.0), and powdered
4 .ANG. molecular sieves. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 to yield a solution approximately 0.1 M in phenol
or aniline, and the Et.sub.3N (5.0 equiv) is added. After stirring
the colored heterogeneous reaction mixture for 24 h at 25.degree.
C. under ambient atmosphere, the resulting slurry was filtered and
the diaryl ether or diaryl amine was isolated from the organic
filtrate by flash chromatography.
General Procedure H
[0343] To a solution of a phenol (1.0 mmol) in DMF (5 mL) was added
an alkyl halide (1.2 mmol) (a catalytic amount of NaI is added for
alkyl chlorides), and potassium carbonate (2.5 mmol) and the
mixture heated at 70.degree. C. overnight. After completion of the
reaction, 5 mL of ethyl acetate and 5 mL of water was added. The
organic layer was washed with water, and then dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuum to afford the
ether, which was purified by flash chromatography.
General Procedure I
[0344] To a solution of ester in THF was added lithium hydroxide
(3-4 eq), water, and methanol. The ratio of THF/water/methanol is
4:1:1. The reaction mixture was stirred at rt for 1-1.5 h. A 10%
solution of citric acid was added to adjust the pH between 6-7.
Ethyl acetate was added and the organic layer is separated. The
aqueous layer was extracted with ethyl acetate twice. The combined
organic layer washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure to give the product.
General Procedure J
[0345] To a stirring solution of an aniline (2 mmol) dissolved in
DCM containing pyridine (4 mmol) was added acid chloride (2.5 mmol)
at 0.degree. C. The reaction mixture was stirred at rt for 3 h,
extracted with DCM, washed with 1M HCl and brine, and evaporation
followed by column chromatography purification gave the amide.
General Procedure K
[0346] To a stirring solution of amine or aniline (1 mmol)
dissolved in DCM containing triethyl amine (4 mmol), was added a
chloroformate (1.5 mmol) at rt. The reaction mixture was stirred
for 1-1.5 h. The reaction mixture was concentrated and purified by
chromatography to give the carbamate.
General Procedure L
[0347] To a stirring solution of amine or aniline (1 mmol)
dissolved in DCM containing DIEA (4 mmol) was added an isocyanate
(1.5 mmol) at rt. The reaction mixture was stirred for 1-1.5 h. The
reaction mixture was concentrated and purified by chromatography to
give the urea.
General Procedure M
[0348] A solution of an aryl bromide or heteroaryl bromide (1 mmol)
and Pd(PPh.sub.3).sub.4 (10 mol %) in anhydrous dioxane was
degassed by bubbling N.sub.2 gas into the solution for 10 min. To
this was added alkenyl tin (1.2 mmol) and the solution was degassed
for an additional 10 min and then heated at 80.degree. C. overnight
under N.sub.2 atmosphere. The reaction was cooled to rt and KF
solution was added and the reaction mixture was stirred for 30 min.
The precipitated solid was filtered and the solid residue on the
filter funnel was washed with copious amounts ethyl acetate to
strip the product. The filtrate was concentrated and purified by
flash column chromatography (silica, Hex:EtOAc) to provide the
corresponding coupled product. This was hydrolyzed as described in
the general procedure C to yield the acid.
General Procedure N
[0349] To a solution of an alkene in anhydrous methanol or ethyl
acetate was added Pd/C (10 wt %) and the reaction was stirred for
2-18 h under an atmosphere of H.sub.2 gas (1 atm). For some alkene
substrates, the reaction was performed under 3-4 atm pressure of
H.sub.2 gas. The reaction mixture was filtered on a celite pad and
washed with methanol. The filtrate was concentrated under reduced
pressure to afford the desired reduced product.
[0350] The above general methods are for illustration only.
Alternate conditions that may optionally be used include: Use of
alternative solvents, alternative stoichiometries of reagents,
alternative reaction temperatures and alternative methods of
purification.
EXAMPLES
[0351] LC-MS data was obtained using gradient elution on a parallel
MUX.TM. system, running four Waters 1525 binary HPLC pumps,
equipped with a Mux-UV 2488 multichannel UV-Vis detector (recording
at 215 and 254 nM) and a Leap Technologies HTS PAL Auto sampler
using a Sepax GP-C18 4.6.times.50 mm column. A three minute
gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05%
TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100%
B. The system is interfaced with a Waters Micromass ZQ mass
spectrometer using electrospray ionization. All MS data was
obtained in the positive mode unless otherwise noted. 1H NMR data
was obtained on a Varian 400 MHz spectrometer.
Example E-1
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[0352] ##STR105##
[0353] To a stirring of solution of H-Tyr(O-tert-Bu)-OMe HCl (15 g,
52.1 mmol), NEt.sub.3 (13.1 g, 129.7 mmol) in 400 mL of DCM at
0.degree. C. was added cyclopentyl acetyl chloride (8.4 g, 57.3
mmol). The reaction mixture was warmed to rt and stirring was
continued for 45 min. Then the organic layer washed with water, 1.0
N HCl and brine then dried over Na.sub.2SO.sub.4. Evaporation of
the solvent gave 19 g of amide, which was used for further step
without purification.
[0354] LCMS: 438 (M+1).sup.+
[0355] To a stirring solution of above amide (19 g, 52.1 mmol) in
400 mL of anhydrous DCM at 0.degree. C. was added oxalyl chloride
(7.9 g, 63.1 mmol). The reaction mixture was brought to rt and
stirring continued for another one hour. Then the reaction mixture
was cooled to -10.degree. C. and to it anhydrous FeCl.sub.3 (10.1
g, 62.3 mmol) was added portion wise. The stirring was continued
for 12 h at rt and the reaction mixture was treated with 200 mL of
2.0 M HCl for 2 h. The organic layer was separated washed with
water and brine, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Methanol (400 mL) and conc. H.sub.2SO.sub.4 (10
mL) was added to the foamy residue and reaction was heated to
reflux for 12 h, methanol was evaporated and the crude product was
extracted with ethyl acetate (2.times.100 mL). The aqueous layer
was basified with NH.sub.4OH (pH>9) and extracted with DCM
(2.times.100 mL). The organic layer washed with water and brine and
dried over Na.sub.2SO.sub.4 evaporation of the solvent gave 7.0 g
of
1-cyclopentylmethyl-7-hydroxy-3,4-dihydro-isoquinoline-3-carboxylic
acid methyl ester.
[0356] LCMS: 288 (M+1).sup.+
[0357] The above compound (7 g, 24.3 mmol) was dissolved in 200 mL
of DCM, then 8.8 g (48.6 mmol) of copper (II) acetate and 12.3 g
(121 mmol) of NEt.sub.3 was added. The resulting mixture was
stirred at rt for 2.0 h, filtered, and the filtrate was
concentrated followed by column chromatography using ethyl acetate
and hexane to give 6.6 g of
1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid methyl
ester.
[0358] LCMS: 286 (M+1).sup.+
[0359] 3.0 g (10.5 mmol) of above phenol, 2.7 g (15.7 mmol) of
4-tert-butyl phenylboronic acid, 1.9 g (10.5 mmol) of copper (II)
acetate and 1 g of crushed 4 .ANG. molecular sieves were taken up
in 115 mL of DCM. To this stirring solution 5.3 g (115 mmol) of
NEt.sub.3 was added and stirring was continued for 12 h. Filtration
and evaporation of the solvent followed by column chromatography
using hexane and ethyl acetate as eluant gave 1.5 g of
7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid methyl ester.
[0360] LCMS: 418 (M+1).sup.+
[0361] To a stirring solution of 1.5 g (3.6 mmol) of ester in 9.0
mL of THF and 2.16 mL of MeOH was added 2.16 mL of 2 N LiOHat rt.
Stirring was continued for 30 min and the mixture was acidified
with 1.0 N HCl (pH=.about.3) and extracted with 2.times.25 mL of
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and concentrated to give 1.37 g of title compound as a
light yellow solid.
[0362] .sup.1H-NMR (400 MHZ, CDCl.sub.3): .delta. 8.47 (s, 1H),
7.98 (d, 1H), 7.59 (s, 1H), 7.53 (dd, 1H), 7.46 (d, 2H), 7.05 (d,
2H), 3.15 (d, 2H), 2.35 (m, 1H), 1.67 (m, 4H), 1.53 (m, 2H), 1.36
(s, 9H), 1.30 (m, 2H). LCMS: 404 (M+1).sup.+
Example E-2
3-(5-bromo-thiophene-2-yl)-2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl
ester
[0363] ##STR106##
[0364] The title compound was prepared by treatment of Compound E-1
with (2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl
ester HCl prepared from commercially available
(2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid according to
general procedure A.
Example E-3
7-(trans-4-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-ca-
rboxylic acid
[0365] ##STR107##
[0366] 0.7 g (2.5 mmol) of
1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid methyl
ester (prepared in example E-1), 3.0 g (5.0 mmol) of triphenyl
phosphine polystyrene resin (1.10 mmol/g) and 0.42 g (2.7 mmol) of
cis-4-tert-butylcyclohexanol were taken in 25 mL of DCM. To this
was added DIAD (0.6 g, 3.0 mmol) at 0.degree. C. The reaction
mixture was shaken for 2 h. Filtration and evaporation of the
solvent followed by column chromatography using hexane/ethyl
acetate gave 0.75 g of product, which was hydrolyzed as described
in general procedure C to afford 669 mg of the title compound as a
light yellow solid.
[0367] LCMS: 410 (M+1).sup.+
Example E-4
6-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[0368] ##STR108##
[0369] 12.5 g (54.3 mmol) of 2-amino-3-(3-hydroxy-phenyl)-propionic
acid methyl ester was reacted with cyclopentyl acetic acid (6.97 g,
54.3 mmol) as described in general procedure A. The compound was
purified using gradient elution with ethyl acetate in hexanes to
yield 9.1 g of
2-(2-cyclopentyl-acetylamino)-3-(3-hydroxy-phenyl)-propionic acid
methyl ester.
[0370] LCMS 307 (M+1).sup.+.
[0371] A portion of the material from the previous step (4.0 g,
13.1 mmol) was dissolved in 120 mL anhydrous DCM, and to this was
added 4-tert-butylphenyl boronic acid (2.0 eq., 26.2 mmol, 4.66 g),
copper (II) acetate (1.1 eq., 14.4 mmol, 2.62 g), and 2.0 g of
powdered 4 .ANG. molecular sieves. To the stirring mixture was
added triethylamine (3.0 eq., 39.3 mmol, 5.5 mL) and the reaction
carried out according to general procedure G. Chromatographic
purification on silica eluting with ethyl acetate in hexanes
afforded 2.50 g of
3-[3-(4-tert-butyl-phenoxy)-phenyl]-2-(2-cyclopentyl-acetylamino)-propion-
ic acid methyl ester.
[0372] LCMS: 439 (M+1).sup.+.
[0373] 1.77 g (4.07 mmol) of
3-[3-(4-tert-butyl-phenoxy)-phenyl]-2-(2-cyclopentyl-acetylamino)-propion-
ic acid methyl ester was dissolved in 40 mL anhydrous toluene and
phosphoryl chloride was added and the mixture heated at 90.degree.
C. for several hours and then cooled. The solvent and excess
reagent was removed and the residue was purified via column
chromatography on silica eluting with 20-30% ethyl acetate in
hexanes to afford 380 mg of the cyclized product,
6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-3,4-dihydro-isoquin-
oline-3-carboxylic acid methyl ester.
[0374] LCMS 421 (M+1).sup.+.
[0375] The product of the previous reaction (380 mg, 0.91 mmol) was
dissolved in 9 mL dry DCM and triethylamine (5.0 eq., 4.53 mmol,
0.63 mL) and copper (II) acetate (2.2 eq., 1.99 mmol, 362 mg) was
added and the mixture stirred at rt for several hours. The solution
was concentrated and purified via column chromatography on silica
eluting with ethyl acetate/hexanes to afford 378 mg of
6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid methyl ester.
[0376] LCMS 419 (M+1).sup.+.
[0377] The above material was taken in its entirety (378 mg, 0.905
mmol) and hydrolyzed according to general procedure C to afford the
title compound as a white solid (365 mg).
[0378] LCMS 405 (M+1).sup.+.
Example E-5
2(R)-Amino-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl
ester HCl
[0379] ##STR109##
[0380] To a suspension of
(2R)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester
HCl (14.0 g, 46.59 mmol) (prepared from commercially available
(2R)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid) in DCM (250
mL) was added NaHCO.sub.3 (9.78 g, 116.49 mmol), water (100 mL).
The solution was stirred for 10 min and Boc-anhydride (12.20 g,
55.91 mmol) was added. The reaction was stirred overnight. The
organic layer was separated and washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
17.0 g of
3-(5-bromo-thiophen-2-yl)-2(R)-tert-butoxycarbonylamino-propionic
acid methyl ester.
[0381] 15.0 g (41.17 mmol) of
3-(5-bromo-thiophen-2-yl)-2(R)-tert-butoxycarbonylamino-propionic
acid methyl ester was treated with tributyl-isopropenyl-stannane
(17.88 g, 54.07 mmol) and Pd(PPh.sub.3).sub.4 (4.8 g, 4.15 mmol) as
described in the general procedure M to afford 8.50 g of
2(R)-tert-butoxycarbonylamino3-(5-isopropenyl-thiophen-2-yl)-propionic
acid methyl ester.
[0382] 8.50 g of
2(R)-tert-butoxycarbonylamino3-(5-isopropenyl-thiophen-2-yl)-propionic
acid methyl ester was treated with Pd/C and H.sub.2 gas (1 atm) by
the general procedure N to afford 8.20 g of
2(R)-tert-butoxycarbonylamino3-(5-isopropyl-thiophen-2-yl)-propionic
acid methyl ester. This ester was treated with HCl/dioxane (4.0 M)
to afford 7.10 g of title compound.
Example E-6
2(S)-Amino-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl
ester HCl
[0383] ##STR110##
[0384] The title compound was prepared by analogous procedure used
to prepare Compound E-5.
Example E-7
7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3-carboxyl-
ic acid
[0385] ##STR111##
[0386] The title compound was synthesized by analogous procedure
used to prepare Compound E-1 with the exception that
tetrahydro-pyran-4-carbonyl chloride was used instead of
cyclopentylacetyl chloride.
Example E-8
1-Cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-carboxyli-
c acid
[0387] ##STR112##
[0388] To a solution of Compound E-1 (1.0 mmol) in THF was added
4-isopropyl cyclohexanol (1.5 mmol), triphenyl phosphine
polystyrene resin (1.10 mmol/g, 2.50 mmol), and DIAD (2 mmol) at
0.degree. C. The reaction was warmed to rt and stirred for 4 h. The
reaction mixture was filtered and concentrated. The crude product
was purified by flash column chromatography (silica, Hexanes/EtOAc
to afford
1-cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-carboxyl-
ic acid methyl ester. This ester was hydrolyzed by the general
procedure C to afford the title compound.
Example E-9
1-Cyclopentylmethyl-7-(4-trans-ethyl-cyclohexyloxy)-isoquinoline-3-carboxy-
lic acid
[0389] ##STR113##
[0390] The title compound was prepared by analogous procedure used
to prepare Compound E-8 with the exception that
4-Cis-4-ethyl-cyclohexanol was used.
Example E-10
7-(4-tert-Butylphenoxy)-isoquinoline-3-carboxylic acid
[0391] ##STR114##
[0392] To a solution of
(3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester (1.47 g, 5.0 mmol) in dry DMF (25 mL) at ambient
temperature, was added iodomethane (1.2 eq., 6.0 mmol, 0.37 mL) and
diisopropylethylamine (1.5 eq. 7.5 mmol, 1.31 mL) in succession,
and the reaction mixture was stirred at rt for 3-4 hours, at which
point LC/MS analysis showed the presence of product. The reaction
mixture was poured into 50 mL of water and extracted with DCM
(3.times.50 mL) and the combined DCM extracts were washed with
water (3.times.50 mL) and brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude product was purified by flash column chromatography on
silica (ethyl acetate/hexanes) to afford
(3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid
2-tert-butyl ester 3-methyl ester (1.13 g).
[0393] LCMS: 308 (M+1).sup.+.
[0394] The above phenol (1.20 g, 3.91 mmol) was reacted with
4-(tert-butyl)phenylboronic acid (1.6 eq., 6.26 mmol, 1.11 g),
copper (II) acetate (1.0 eq. 3.91 mmol, 710 mg) as described in
general procedure G. Flash column chromatography on silica (ethyl
acetate/hexanes) provided 750 mg of the desired product,
(3S)-7-(4-tert-butylphenoxy)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic
acid 2-tert-butyl ester 3-methyl ester.
[0395] LCMS: 440 (M+1).sup.+
[0396] A portion of the material described above (400 mg, 0.91
mmol) was placed in a dry 4 dram vial containing a magnetic stir
bar, and was treated with a 4N solution of anhydrous HCl in
1,4-dioxane (1.0 mL, 4.0 mmol, 4.4 eq). The reaction was stirred at
ambient temperature for 1 hour, until complete by TLC. The solvent
and residual HCl was removed under vacuum and the crude product,
(3S)-7-(4-tert-butylphenoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid methyl ester hydrochloride, was used without further
purification.
[0397] LCMS: 340 (M+1).sup.+
[0398] The above crude product was dissolved in 18 mL of dry
toluene and DDQ (3.0 eq., 2.73 mmol, 620 mg) was added in a single
portion. The mixture was heated at reflux for 2 hours then cooled
to rt and concentrated under reduced pressure. The crude residue
was placed directly atop a silica gel column and eluted with a
mixture of ethyl acetate and hexanes to furnish 229 mg of,
7-(4-tert-butylphenoxy)-isoquinoline-3-carboxylic acid methyl
ester. A portion of the ester (208 mg, 0.62 mmol) was hydrolyzed as
described in general procedure C to afford 199 mg of the title
compound as a white solid.
[0399] .sup.1H-NMR (400 MHZ, CDCl.sub.3): .delta. 8.47 (s, 1H),
7.98 (d, 1H), 7.59 (s, 1H), 7.53 (dd, 1H), 7.46 (d, 2H), 7.05 (d,
2H), 3.15 (d, 2H), 2.35 (m, 1H), 1.67 (m, 4H), 1.53 (m, 2H), 1.36
(s, 9H), 1.30 (m, 2H). LCMS: 322 (M+1).sup.+.
Example E-11
[(5-Bromo-thiophen-2-ylmethyl)-amino]-acetic acid tert-butyl
ester
[0400] ##STR115##
[0401] The title compound was prepared by treatment of
5-bromo-thiophene-2-carboxyaldehyde with amino-acetic acid
tert-butyl ester by the general procedure E.
Example E-12
[(5-Bromo-thiophen-2-ylmethyl)-amino]-acetic acid methyl ester
[0402] ##STR116##
[0403] The title compound was prepared by treatment of
5-bromo-thiophene-2-carboxyaldehyde with amino-acetic acid methyl
ester by the general procedure E.
Example E-13
[(4-Bromo-thiophen-2-ylmethyl)-amino]-acetic acid methyl ester
[0404] ##STR117##
[0405] The title Compound was prepared by treatment of
4-bromo-thiophene-2-carboxyaldehyde with amino-acetic acid methyl
ester by the general procedure E.
Example E-14
[(5-Methyl-thiophen-2-ylmethyl)-amino]-acetic acid methyl ester
[0406] ##STR118##
[0407] The title compound was prepared by treatment of
5-methyl-thiophene-2-carboxyaldehyde with amino-acetic acid methyl
ester by the general procedure E.
Example 1
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-phenylthiophen-2-yl)-propionic acid
[0408] The title compound was prepared by treatment of Compound E-2
with phenyl boronic acid by the general procedure D to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-phenylthiophen-2-yl)-propionic acid methyl ester.
The ester was hydrolyzed by the general procedure C to afford the
title compound.
[0409] LCMS: 624 (M+1).sup.+
Example 2
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-[5-(4-trifluoromethyl-phenyl)thiophen-2-yl]-propionic
acid
[0410] The title compound was prepared by treatment of Compound E-2
with 4-trifluorophenylboronic acid by the general procedure D to
yield
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-trifluoromethyl-phenyl)thiophen-2-yl]-propionic
acid methyl ester. The ester was hydrolyzed by the general
procedure C to obtain the title compound.
[0411] LCMS: 702 (M+1).sup.+
Example 3
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid
methyl ester
[0412] The title compound was prepared by treatment of Compound E-2
with cyclopenten-1-ylboronic acid by the general procedure D.
[0413] LCMS: 638 (M+1).sup.+
Example 4
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid
[0414] Example 3 was hydrolyzed by the general procedure C to
obtain the title compound.
[0415] LCMS: 624 (M+1).sup.+
Example 5
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid methyl
ester
[0416] The title compound was prepared by the treatment of Example
3 with Pd/C and H.sub.2 gas (1 atm) by the general procedure N.
[0417] LCMS: 640 (M+1).sup.+
Example 6
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid
[0418] The title compound was prepared by hydrolysis of Example 5
by the general procedure C.
[0419] LCMS: 626 (M+1).sup.+
Example 7
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-furan-3-yl-thiophen-2-yl)-propionic acid
[0420] The title compound was prepared by treatment of Compound E-2
with furan-3-boronic acid to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-furan-3-yl-thiophen-2-yl)-propionic acid methyl
ester. The ester was hydrolyzed by the general procedure C to
obtain the title compound.
[0421] LCMS: 624 (M+1).sup.+
Example 8
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-[5-(4-isopropyphenyl)-thiophen-2yl]proprionic acid
[0422] The title compound was prepared by treatment of Compound E-2
with 4-isopropylphenylboronic acid to yield
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-isopropyphenyl)-thiophen-2yl]proprionic acid
methyl ester. The ester was hydrolyzed by the general procedure C
to afford the title compound.
[0423] LCMS: 676 (M+1).sup.+
Example 9
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-vinyl-thiophen-2-yl)-propionic acid
[0424] The title compound was prepared by treatment of Compound E-2
with tributyl vinyl stannane and Pd(PPh.sub.3).sub.4 by the general
procedure M to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-vinylthiophen-2-yl)-propionic acid methyl ester.
The ester was hydrolyzed by the general procedure C to afford the
title compound.
[0425] LCMS: 584 (M+1).sup.+
Example 10
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-p-tolyl-thiophen-2-yl)-propionic acid
[0426] The title compound was prepared by treatment of Compound E-2
with 4-methylphenylboronic acid by the general procedure D to
afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-p-tolyl-thiophen-2-yl)-propionic acid methyl ester.
The ester was hydrolyzed by the general procedure C to afford the
title compound.
[0427] LCMS: 648 (M+1).sup.+
Example 11
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-[5-(4-chloro-phenyl)-thiophen-2-yl]-propionic acid
[0428] The title compound was prepared by treatment of Compound E-2
with 4-chlorophenylboronic acid by the general procedure D to
afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(4-chloro-phenyl)-thiophen-2-yl]-propionic acid
methyl ester. The ester was hydrolyzed by the general procedure C
to afford the title compound.
[0429] LCMS: 668 (M+1).sup.+
Example 12
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-ethyl-thiophen-2-yl)-propionic acid
[0430] The title compound was prepared by the treatment of Example
9 with Pd/C and H.sub.2 (1 atm) by the general procedure N.
[0431] LCMS: 586 (M+1).sup.+
Example 13
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-furan-2-yl-propionic acid
[0432] Compound E-1 (0.050 g (0.012 mmol) was reacted with
(2S)-amino-3-furan-2-yl-propionic acid methyl ester HCl (0.038 g,
0.018 mmol, prepared from commercially available
(2S)-amino-3-furan-2-yl-propionic acid) as described in general
procedure A to afford 0.066 g of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-furan-2-yl-propionic acid methyl ester.
[0433] The resulting ester was hydrolyzed by the general procedure
C to afford 0.060 g of the title compound.
[0434] LCMS: 542 (M+1).sup.+
Example 14
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(2-trifluoromethyl-phenyl)-propionic acid
[0435] The title compound was prepared by analogous procedure used
to prepare Example 13 with the exception that
2(S)-Amino-3-(2-trifluoromethyl-phenyl)-propionic acid methyl ester
HCl (prepared from commercially available
2(S)-Amino-3-(2-trifluoromethyl-phenyl)-propionic acid) was
used.
[0436] The resulting ester was hydrolyzed by the general procedure
C to afford the title compound.
[0437] LCMS: 620 (M+1).sup.+
Example 15
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmeth-
yl-isoquinoline-3-carbonyl]-amino}-acetic acid tert-butyl ester
[0438] Compound E-11 (0.060 g, 0.195 mmol) was treated with
Compound E-1 (0.079 g, 0.195 mmol) by the general procedure A to
afford 36 mg of the title compound.
[0439] LCMS: 693 (M+1).sup.+
Example 16
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(3,5-difluorophenyl-propionic acid
[0440] The title compound was prepared by analogous procedure used
to prepare Example 13 with the exception that
2(S)-Amino-3-(3,5-difluorophenyl)-propionic acid methyl ester HCl
(prepared from commercially available
2(S)-Amino-3-(3,5-difluorophenyl)-propionic acid) was used.
[0441] The resulting ester was hydrolyzed by the general procedure
C to afford the title compound.
[0442] LCMS: 588 (M+1).sup.+
Example 17
[[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(5-
-methyl-thiophen-2-ylmethyl)-amino]-acetic acid
[0443] Compound E-14 was treated with Compound E-1 by the general
procedure A to yield
[[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(-
5-methyl-thiophen-2-ylmethyl)-amino]-acetic acid methyl ester,
which upon hydrolysis by the general procedure C gave the title
compound.
[0444] LCMS: 572 (M+1).sup.+
Example 18
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmeth-
yl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester
[0445] Compound E-12 was treated with Compound E-1 by the general
procedure E to afford the title compound.
[0446] LCMS: 651 (M+1).sup.+
Example 19
{(4-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmeth-
yl-isoquinoline-3-carbonyl]-amino}-acetic acid
[0447] Compound E-13 was treated with Compound E-1 by the general
procedure A to yield
{(4-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester which
upon hydrolysis by the general procedure C gave the title
compound.
[0448] LCMS: 637 (M+1).sup.+
Example 20
{(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmeth-
yl-isoquinoline-3-carbonyl]-amino}-acetic acid
[0449] Example 18 was hydrolyzed by the general procedure C to
afford the title compound.
[0450] LCMS: 637 (M+1).sup.+
Example 21
Benzo[b]thiophen-3-yl-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoqu-
inoline-3-carbonyl]-amino}-acetic acid
[0451] The title compound was prepared by analogous procedure used
to prepare Example 13 with the exception that
amino-benzo[b]thiophen-3-yl-acetic acid methyl ester HCl (obtained
from commercially available amino-benzo[b]thiophen-3-yl-acetic
acid) was used.
[0452] The resulting ester was hydrolyzed by the general procedure
C to afford the title compound.
[0453] LCMS: 594 (M+1).sup.+
Example 22
2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(4-fluoro-phenyl)-propionic acid
[0454] The title compound was prepared by analogous procedure use
to prepare Example 13 with the exception that
2(S)-amino-3-(4-fluoro-phenyl)-propionic acid methyl ester HCl
(obtained from commercially available
2(S)-amino-3-(4-fluoro-phenyl)-propionic acid) was used.
[0455] The resulting ester was hydrolyzed by the general procedure
C to afford the title compound.
[0456] LCMS: 570 (M+1).sup.+
Example 23
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-propenylthiophen-2-yl)-propionic acid
[0457] Compound E-2 was treated with tributyl-propenyl-stannane by
the general procedure M to yield
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propenylthiophen-2-yl)-propionic acid methyl ester.
The ester was hydrolyzed by the general procedure C to afford the
title compound.
[0458] LCMS: 598 (M+1).sup.+
Example 24
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-propylthiophen-2-yl)-propionic acid
[0459] The title compound was prepared by treatment of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propenylthiophen-2-yl)-propionic acid methyl ester
(prepared in Example 23) with Pd/C and H.sub.2 (1 atm) by the
general procedure N to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-propylthiophen-2-yl)-propionic acid methyl ester.
The ester was hydrolyzed by the general procedure C to afford the
title compound.
[0460] LCMS: 600 (M+1).sup.+
Example 25
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-(3,3-dimethyl-but-1-enyl)-thiophen-2-yl)-propionic
acid
[0461] Compound E-2 was treated with
tributyl-(3,3-dimethyl-but-1-enyl)-stannane by the general
procedure M to yield
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3--
carbonyl]-amino}-3-(5-(3,3-dimethyl-but-1-enyl)-thiophen-2-yl)-propionic
acid methyl ester. The ester was hydrolyzed by the general
procedure C to afford the title compound.
[0462] LCMS: 640 (M+1).sup.+
[0463] Examples 26
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-[5-(hydroxymethylthiophen-2-yl]-propionic acid methyl
ester (example 26)
[0464] To a solution of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-vinylthiophen-2-yl)-propionic acid methyl ester
(prepared in Example 9) (0.650 g, 1.09 mmol) in acetone:water was
added methylmorpholine-N-oxide (0.340 mL) and osmium tetroxide (2
crystals). The solution was stirred at 0.degree. C. for 1.5 h.
Ethyl acetate was added and extracted with a solution of
Na.sub.2S.sub.2O.sub.4(satd), brine, dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure to give 0.600 g of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(1,2-dihydroxy-ethyl)-thiophen-2-yl]-propionic acid
methyl ester.
[0465] To a solution of this methyl ester (0.600 g, 0.954 mmol) in
THF:water (1:1, 7 mL) was added NaIO.sub.4 (0.816 g, 3.817 mmol) at
0.degree. C. The reaction was stirred at 0.degree. C. for 1.5 h.
EtOAc was added and the organic layer was separated and washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure to give product as an oil. The crude product was purified
by flash column chromatography (silica, Hex:EtOAc) to give 0.220 g
of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(formyl-thiophen-2-yl]-propionic acid methyl
ester.
[0466] To a solution of this methyl ester (0.060 g, 0.100 mmol) in
anhydrous methanol (1.5 mL) was added NaBH.sub.4 (15 mg) at
0.degree. C. The reaction was stirred at 0.degree. C. for 20 min.
LCMS showed approximately 25% reduction of the ester group in the
desired product to alcohol. The reaction mixture was concentrated
and purified by flash column chromatography (silica, Hex:EtOAc) to
yield 22 mg of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(hydroxymethylthiophen-2-yl]-propionic acid methyl
ester (Example 26).
[0467] Example 26--LCMS: 602 (M+1).sup.+
Example 27
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-[5-(hydroxymethylthiophen-2-yl]-propionic acid
[0468] This was prepared by the hydrolysis of Example 26 by the
general procedure C to afford the title compound.
[0469] LCMS: 588 (M+1).sup.+
Example 28
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-[5-(methyl-thiophen-2-yl]-propionic acid
[0470] To a solution of Example 26 (0.060 g, 0.100 mmol), was added
4 .ANG. MS and TMSCl (0.076 mL). To this was added NaBH.sub.3CN
(0.038 g, 0.601 mmol) at 0.degree. C. The solution was warmed to rt
and stirred for 18 h. The crude reaction mixture was purified by
flash column chromatography (silica, Hex:EtOAc) to afford 8.5 mg of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-[5-(methyl-thiophen-2-yl]-propionic acid methyl ester.
This ester was hydrolyzed by the general procedure C to afford 5.0
mg of the title compound.
[0471] LCMS: 572 (M+1).sup.+
Example 29
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropenylthiophen-2-yl)-propionic acid
[0472] The title compound was prepared by treatment of Compound E-2
with tributyl-isopropenyl-stannane and Pd(PPh.sub.3).sub.4 as
described in the general procedure M to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropenylthiophen-2-yl)-propionic acid methyl
ester. This ester was hydrolyzed by the general procedure C to
afford the title compound.
[0473] LCMS: 598 (M+1).sup.+
Example 30
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid
[0474] The title compound was prepared by the treatment of
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropenylthiophen-2-yl)-propionic acid methyl
ester (prepared in Example 29) with Pd/C and H.sub.2 gas (1 atm) by
the general procedure N to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid methyl
ester. This ester was hydrolyzed by the general procedure C to
afford the title compound.
[0475] LCMS: 600 (M+1).sup.+
Example 31
3-(5-bromo-thiophene-2-yl)-2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid
[0476] Compound E-1 (0.150 g, 0.37 mmol) was reacted with
(2R)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester
HCl (0.145 g, 0.482 mmol), prepared from commercially available
(2R)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid) as described
in general procedure A to afford 0.180 g of
3-(5-bromo-thiophene-2-yl)-2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylm-
ethyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
This resulting ester was hydrolyzed by the general procedure C to
afford 0.158 g of the title compound.
[0477] LCMS: 637 (M+1).sup.+
Example 32
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-chloro-thiophen-2-yl)-propionic acid
[0478] Compound E-1 was treated with
2(R)-amino-3-(5-chloro-thiophen-2-yl)-propionic acid methyl ester
(obtained from commercially available
2(R)-amino-3-(5-chloro-thiophen-2-yl)-propionic acid) by the
general procedure A to obtain
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-chloro-thiophen-2-yl)-propionic acid methyl ester.
The ester was hydrolyzed by the general procedure C to obtain the
title compound.
[0479] LCMS: 592 (M+1).sup.+
Example 33
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-chloro-furan-2-yl)-propionic acid
[0480] Compound E-1 was treated with
2(S)-amino-3-(5-chloro-furan-2-yl)-propionic acid methyl ester HCl
(obtained from commercially available
2(S)-amino-3-(5-chloro-furan-2-yl)-propionic acid) by the general
procedure A to obtain
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-chloro-furan-2-yl)-propionic acid methyl ester. The
ester was hydrolyzed by the general procedure C to obtain the title
compound.
[0481] LCMS: 576 (M+1).sup.+
Example 34
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(2,5-dichloro-thiophen-3-yl)-propionic acid
[0482] Compound E-1 was treated with
2(S)-amino-3-(2,5-dichloro-thiophen-3-yl)-propionic acid methyl
ester HCl (obtained from commercially available
2(S)-amino-3-(2,5-dichloro-thiophen-3-yl)-propionic acid) by the
general procedure A to obtain
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(2,5-dichloro-thiophen-3-yl)-propionic acid methyl
ester. The ester was hydrolyzed by the general procedure C to
obtain the title compound.
[0483] LCMS: 626 (M+1).sup.+
Example 35
(5-Bromo-thiophen-2-yl)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-iso-
quinoline-3-carbonyl]-amino}-acetic acid
[0484] Compound E-1 was treated with
amino-(5-bromo-thiophen-2-yl)-acetic acid methyl ester (obtained
from commercially available amino-(5-bromo-thiophen-2-yl)-acetic
acid) by the general procedure A to obtain
(5-Bromo-thiophen-2-yl)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester. The
ester was hydrolyzed by the general procedure C to obtain the title
compound.
[0485] LCMS: 622 (M+1).sup.+
Example 36
3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-
-isoquinoline-3-carbonyl]-amino}-propionic acid
[0486] Compound E-1 was treated with
2(S)-amino-(5-bromo-furan-2-yl)-propionic acid methyl ester HCl
(obtained from commercially available
2(S)-amino-(5-bromo-furan-2-yl)-propionic acid) by the general
procedure A to obtain
3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethy-
l-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester. The
ester was hydrolyzed by the general procedure C to obtain the title
compound.
[0487] LCMS: 620 (M+1).sup.+
Example 37
3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cy-
clopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid
[0488] Compound E-3 was treated with
(2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester
HCl (prepared from commercially available
(2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid) by the general
procedure A to afford
3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-c-
yclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid
methyl ester. The ester was hydrolyzed by the general procedure C
to afford the title compound.
[0489] LCMS: 642 (M+1).sup.+
Example 38
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmet-
hyl-isoquinoline-3-carbonyl]-amino}-propionic acid
[0490] Compound E-4 was treated with
(2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid methyl ester
HCl (prepared from commercially available
(2S)-amino-3-(5-bromo-thiophen-2-yl)-propionic acid) by the general
procedure A to afford
3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
This ester was hydrolyzed by the general procedure C to afford the
title compound.
[0491] LCMS: 636 (M+1).sup.+
Example 39
2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoli-
ne-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic
acid
[0492]
3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexylo-
xy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic
acid methyl ester (prepared in Example 37) was treated with
tributyl-isopropenyl-stannane and Pd(PPh.sub.3).sub.4 by the
general procedure M to afford
2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinol-
ine-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic
acid methyl ester. This ester was hydrolyzed by the general
procedure C to afford the title compound.
[0493] LCMS: 604 (M+1).sup.+
Example 40
2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoli-
ne-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic
acid
[0494]
2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cyclopentylmethyl-is-
oquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic
acid methyl ester (prepared in Example 39) was treated with Pd/C
and H.sub.2(1 atm) by the general procedure N to afford
2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinol-
ine-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
methyl ester. This ester was hydrolyzed by the general procedure C
to afford the title compound.
[0495] LCMS: 606 (M+1).sup.+
Example 41
2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropyl-furan-2-yl)-propionic acid
[0496] A solution of Compound E-1 (1 mmol) in DMF was treated with
2(S)-Amino-3-(5-bromo-furan-2-yl)-propionic acid methyl ester HCl
(1.2 mmol, prepared from commercially available
2(S)-Amino-3-(5-bromo-furan-2-yl)-propionic acid) by the general
procedure A to yield
3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethy-
l-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
[0497] The above bromide (1 mmol) was treated with
tributyl-isopropenyl-stannane (1.5 mmol) and Pd(PPh.sub.3).sub.4
(10 mol %) by the general procedure M to yield
2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropenyl-furan-2-yl)-propionic acid methyl
ester.
[0498] The above alkene was reduced by the general procedure N to
afford
2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-furan-2-yl)-propionic acid methyl ester.
This ester was hydrolyzed by the general procedure C to afford the
title compound.
[0499] LCMS: 584 (M+1).sup.+
Example 42
2(S)-{[1-cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-ca-
rbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0500] The title compound was prepared by treatment of Compound E-8
(1 mmol) with E-6 (1.20 mmol) by the general procedure A to yield
2(S)-{[1-cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-c-
arbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl
ester. The ester was hydrolyzed by the general procedure C to
afford the title compound.
[0501] LCMS: 592 (M+1).sup.+
Example 43
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid
[0502] 0.370 g (0.570 mmol) of
3-(5-bromo-thiophene-2-yl)-2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylm-
ethyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester
(prepared in Example 31) was reacted with
Tributyl-isopropenyl-stannane (0.330 g, 0.997 mmol) and
Pd(PPh.sub.3).sub.4 (65 mg, 0.057 mmol) by the general procedure M
to yield 0.295 g of coupled alkene product. The resulting alkene
(95 mg) was reduced as described in the general procedure N to
afford 84 mg of
2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid methyl
ester. This ester (75 mg) was hydrolyzed by the general procedure C
to afford 65 mg of the title compound as a white solid. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .quadrature. 8.85 (d, 1H), 8.32 (s, 1H),
7.78 (d, 1H), 7.39 (m, 3H), 7.00 (d, 2H), 6.67 (s, 1H), 6.48 (s,
1H), 4.93 (d, 1H), 3.45 (d, 2H), 2.97 (m, 3H), 2.27 (m, 1H), 1.58
(m, 6H), 1.34 (m, 9H), 1.21 (m, 8H). LCMS: 600 (M+2).sup.+.
[0503] LCMS: 600 (M+1).sup.+
Example 44
2(S)-{[7-(4-tert-Butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopr-
opyl-thiophen-2-yl)-propionic acid
[0504] The title compound was prepared by the treatment of Compound
E-10 (1 mmol) with Compound E-6 (1.2 mmol) by the general procedure
A to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3--
(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester. This ester
was hydrolyzed by the general procedure C to afford title
compound.
[0505] LCMS: 517 (M+1).sup.+
Example 45
2(S)-{[1-Cyclopentylmethyl-7-(4-trans-ethyl-cyclohexyloxy)-isoquinoline-3--
carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0506] The title compound was prepared by treatment of Compound E-9
(1 mmol) with Compound E-6 (1.20 mmol) by the general procedure A
to yield
2(S)-{[1-cyclopentylmethyl-7-(4-ethyl-cyclohexyloxy)-isoquinoline-3-carbo-
nyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl
ester. The ester was hydrolyzed by the general procedure C to
afford the title compound.
[0507] LCMS: 578 (M+1).sup.+
Example 46
2(S)-{[1-cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbonyl-
-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0508] 1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid
methyl ester (prepared in example E-1) was treated with
4-isopropylphenylboronic acid by the general procedure G to yield
7-(4-isopropyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid methyl ester. This ester was hydrolyzed by the general
procedure C to afford
7-(4-isopropyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carb-
oxylic acid. This acid was coupled with Compound E-6 by the general
procedure A to yield
2(S)-{[1-cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbony-
l-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester.
This ester was hydrolyzed by the general procedure C to afford the
title compound.
[0509] LCMS: 586 (M+1).sup.+
Example 47
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3-c-
arbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0510] This was prepared by the treatment of Compound E-7 with
Compound E-6 to afford
2(S)-{[7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3--
carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
methyl ester. The ester was hydrolyzed by the general procedure C
to give the title compound.
[0511] LCMS: 602 (M+1).sup.+
Example 48
2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbony-
l]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0512] 3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl
-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic
acid methyl ester (prepared in Example 38) was treated with
tributyl-isopropenyl-stannane and Pd(PPh.sub.3).sub.4 as described
in the general procedure M to afford
2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid methyl
ester. This was treated with Pd/C and H.sub.2 (1 atm) by the
general procedure N to afford
2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinolin-
e-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
methyl ester. This ester was hydrolyzed by the general procedure C
to afford the title compound.
[0513] LCMS: 600 (M+1).sup.+
Example 49
2(S)-{[7-(4-tert-Butyl-phenyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl-
]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0514] 1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid
methyl ester (prepared in Example E-1) was hydrolyzed by the
general procedure C to afford
1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid. This
acid (1 mmol) was coupled with Compound E-6 to afford
2(S)-[(1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carbonyl)amino]-3-(5--
isopropyl-thiophen-2-yl)-propionic acid methyl ester.
[0515] To a stirring solution of above phenol (1 mmol), Et.sub.3N
(2 mmol) and DMAP (cat.) in DCM was added, followed by excess
trifluoromethanesulfonic anhydride (2 mmol) at 0.degree. C. The
reaction was stirred at rt for 30 min. The organic layer was
separated, washed with citric acid, water, brine, dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure to give
the desired triflate which was used without further purification
for the next step.
[0516] The above triflate (1 mmol) was treated with
4-tert-butylphenylboronic acid (2 mmol), Pd(PPh.sub.3).sub.4 (0.05
mmol) and 2N Na.sub.2CO.sub.3 (3 mmol) solution by the general
procedure D to afford
2(S)-{[7-(4-tert-Butyl-phenyl)-1-cyclopentylmethyl-isoquinoline-3--
carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
methyl ester. This ester was hydrolyzed by the general procedure C
to afford the title compound.
[0517] LCMS: 584 (M+1).sup.+
Example 50
2(S){[7-(4-tert-Butyl-benzoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl-
]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid
[0518] The triflate of Example 49 (1 mmol),
4-tert-butylphenylboronic acid (1.40 mmol), PdCl.sub.2(dppf) (10
mol %), potassium carbonate (3 mmol), and crushed NaI (3 mmol) were
added to a flame dried flask. The flask was flushed with CO gas and
then charged with anisole. The mixture was heated at 80.degree. C.
for 48 h under an atmosphere of CO. The reaction mixture was cooled
to rt, filtered, and washed with EtOAc. The organic layer washed
with water, brine, dried, and concentrated under reduced pressure.
The crude product was purified by flash chromatography (silica,
Hexanes:EtOAc) to give pure
2(S)-{[7-(4-tert-Butyl-benzoyl)-1-cyclopentylmethyl-isoquinoline-3-carbon-
yl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl
ester. The ester was hydrolyzed by the general procedure C to
afford the title compound.
[0519] LCMS: 612 (M+1).sup.+
Example 51
3-(5-Acetyl-thiophen-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylme-
thyl-isoquinoline-3-carbonyl]-amino}-propionic acid
[0520] Compound E-2 (1.0 g, 1.53 mmol) was treated with
tributyl-(1-ethoxy-vinyl)-stannane (0.83 g, 2.3 mmol), and
Pd(PPh.sub.3).sub.4 (0.177 g, 0.15 mmol) by the general procedure M
to yield 0.600 g of
3-(5-Acetyl-thiophen-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylm-
ethyl-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
The ester (20 mg) was hydrolyzed by the general procedure C to
afford the title compound.
[0521] LCMS: 600 (M+1).sup.+
Example 52
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-(5-isopropyl-thiophen-2-ylmethyl)-(2R)-methanesulfonylamino-2-oxo-
-ethyl]-amide
[0522] To a solution of Example 43 (0.150 g, 0.250 mmol) in DCM was
added oxalyl chloride (0.063 g, 0.50 mmol) and the solution was
stirred for 45 min. The solution was concentrated and the solid was
dried under vacuum. The solid was dissolved in DCM and
methanesulfonamide (0.070 g, 0.750 mmol) was added followed by the
NEt.sub.3 (0.100 mL, 0.750 mmol) and the reaction was stirred for 2
h. The solution was concentrated and purified by flash
chromatography (silica, DCM:MeOH) to afford 7 mg of title
compound.
[0523] LCMS: 677 (M+1).sup.+
Example 53
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-(5-isopropyl-thiophen-2-ylmethyl)-(2S)-methanesulfonylamino-2-oxo-
-ethyl]-amide
[0524] To a solution of Example 30 (0.105 g, 0.17 mmol) in THF was
added CDI (0.085 g, 0.526 mmol) and the reaction was stirred at rt
for 6 h. To this was added a solution of methanesulfonamide (0.035
g, 0.36 mmol) and DBU (0.040 g, 0.26 mmol) in THF and the reaction
was heated at 60.degree. C. for 3 h and stirred at rt for 3 h. The
solution was concentrated under reduced pressure and the crude
product was purified by the same procedure as used in Example 52 to
afford 8 mg of the title compound.
[0525] LCMS: 677 (M+1).sup.+
Example 54
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-benzyloxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide
[0526] A solution of Example 43 (0.090 g, 0.150 mmol) in DMF was
treated with o-Benzylhyroxylamine hydrochloride (27 mg, 0.165
mmol), HBTU (0.063 g, 0.165 mmol), and DIEA (0.150 mL, 0.829 mmol)
by the general procedure A. The crude product was purified by flash
chromatography (silica, Hexanes:EtOAc) to afford 74 mg of title
compound.
[0527] LCMS: 705 (M+1).sup.+
Example 55
7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic
acid
[1-hydroxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide
[0528] Example 54 (68 mg, 0.09 mmol) was treated with H.sub.2 (1
atm) and Pd/C by the general procedure N. The crude product was
purified by flash chromatography (silica,
CH.sub.2Cl.sub.2:CH.sub.3OH) to afford 6 mg of title compound.
[0529] LCMS: 615 (M+1).sup.+
Biological Assay
[0530] The following assay methods may be used to identify
compounds of Formula (I or X) that are effective in antagonizing
the function of factor IX. Compounds of Formula (I or X) are
effective in antagonizing the function of factor IX may be as
inhibitors of the intrinsic clotting pathway.
General Assay Procedure
Factor IXa Florescence Based Molecular Assay:
[0531] To determine the IC.sub.50 of compounds of Formula (I or X)
relative to factor IXa, 12 .mu.L solutions of compounds of Formula
(I or X) at various concentrations (2% DMSO final concentration)
were incubated for 10 min at room temp. with a 24 .mu.L solution of
FIXa (HCIXA-0050 Haemotologic Technologies Inc. Essex Junction,
Vt.; 3.9 units/mL) in buffer containing 80% Ethylene glycol, 10 mM
CaCl.sub.2, 200 mM NaCl, and 100 mM Tris (pH 7.4) where the 24
.mu.L solution of FIXa had an activity of 3.9 units/mL. The
reaction was started by the addition of 12 .mu.L of 0.5 mM FIXa
substrate (Pefa-10148 from Pentapharm Basel, Switzerland; methyl
sulfonyl-D-cyclohexylglycyl-glycyl-arginine-7-amino-4-methylcoumar-
id monoacetate, available from Centerchem, Inc.). After incubating
the reaction for 10 min at room temp, the plate was read in a
Spectromax Gemini fluorescence plate reader with and excitation
wavelength of 340 nm and an emission wavelength of 440 nm. From the
varying concentrations of test compound, IC.sub.50's are then
calculated.
Factor XIa Chromogenic Based Molecular Assay:
[0532] To determine the IC.sub.50 of compounds of Formula (I or X)
relative to factor XIa, 20 .mu.L solutions of compounds of Formula
(I or X) at various concentrations (2% DMSO final concentration)
were incubated for 10 min at room temp. with a 10 .mu.L solution of
FXIa (HCXIA-0160 from Haemotologic Technologies Inc. Essex
Junction, Vt.) in buffer containing 50 mM Tris (pH 7.4) and 150 mM
NaCl where the 10 .mu.L solution of FXIa had an activity of 2
units/mL, and 150 .mu.L of buffer. The reaction was started by the
addition of 20 .mu.L of 10 mM FXIa substrate (Pefa-3371 from
Pentapharm Basel, Switzerland; Pyr-Phg-Arg-pNA monoacetate,
available from Centerchem, Inc.). After incubating the reaction for
10 min at room temp, the plate was read in a Spectromax UV/vis
plate reader at 405 nm.
FIXa In Vitro Clotting Assay
[0533] Compounds of Formula (I or X) of the present invention were
evaluated for their inhibition of clotting in plasma to which
exogenous Factor IXa was added. 20 .mu.L solutions of compounds of
Formula (I or X) at various concentrations having 2% DMSO were
incubated with 30 .mu.L FIXa (HCXIA-0160 from Haemotologic
Technologies Inc. Essex Junction, Vt.) 3.2 units/mL in assay buffer
containing 20 mM HEPES (pH 7.4) and 150 mM NaCl, 50 .mu.L of 1:64
dilution of ALEXIN (trinity biosciences) in assay buffer, and 50
.mu.L reconstituted human citrated plasma (Sigma) for 10 min at
37.degree. C. The reaction was started by the addition of 50 .mu.L
of 40 mM CaCl.sub.2 in assay buffer. The plate was read in kinetic
mode at 405 nm and 37.degree. C. immediately after addition of
calcium. The plate was read for 5-10 min (depending on clot time)
in 10 sec intervals on a Spectromax UV/vis plate reader.
FXIa In Vitro Clotting Assay:
[0534] Compounds of Formula (I or X) of the Present Invention Were
Evaluated for Their inhibition of clotting in plasma to which
exogenous Factor XI was added. 20 .mu.L solutions of compounds of
Formula (I or X) at various concentrations having 2% DMSO were
incubated with 30 .mu.L FXIa (HCXIA-0160 from Haemotologic
Technologies Inc. Essex Junction, Vt.) 0.4 units/mL in assay buffer
containing 20 mM HEPES (pH 7.4) and 150 mM NaCl, 50 .mu.L of 1:64
dilution of ALEXIN (trinity biosciences) in assay buffer, and 50
.mu.L reconstituted human citrated plasma (Sigma) for 10 min at
37.degree. C. The reaction was started by the addition of 50 .mu.L
of 40 mM CaCl.sub.2 in assay buffer. The plate was read in kinetic
mode at 405 nm and 37.degree. C. immediately after addition of
calcium. The plate was read for 5-10 min (depending on clot time)
in 10 sec intervals on a Spectromax UV/vis plate reader.
[0535] The Examples in Table 1 either inhibit Factor IX in the
Factor IXa Fluorescence assay, inhibit Factor XI in the Factor XIa
Chromogenic assay, inhibit Factor IX in the Factor IXa in vitro
clotting assay, or inhibit Factor XI in the in vitro clotting assay
with an IC.sub.50 of less than 30 .mu.M. Various Examples in Table
1 may also have IC.sub.50's below 30 .mu.M in more than one of the
above-mentioned assays.
[0536] While the invention has been described and illustrated with
reference to certain preferred embodiments thereof, those skilled
in the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the preferred dosages as set forth herein may be applicable as
a consequence of variations in the responsiveness of the mammal
being treated for factor Ixa-mediated disease(s). Likewise, the
specific pharmacological responses observed may vary according to
and depending on the particular active compound selected or whether
there are present pharmaceutical carriers, as well as the type of
formulation and mode of administration employed, and such expected
variations or differences in the results are contemplated in
accordance with the objects and practices of the present invention.
Moreover, all compounds that are recited in the written description
are contemplated as possibilities for any of the recited methods,
processes, compositions, and/or compounds as appear in the written
description and the appended claims.
* * * * *