U.S. patent application number 11/774358 was filed with the patent office on 2007-11-22 for thrombin receptor antagonists.
This patent application is currently assigned to Schering Corporation. Invention is credited to Samuel Chackalamannil, Mariappan V. Chelliah, Martin C. Clasby, William J. Greenlee, Enrico P. Veltri, Yuguang Wang, Yan Xia.
Application Number | 20070270439 11/774358 |
Document ID | / |
Family ID | 29250954 |
Filed Date | 2007-11-22 |
United States Patent
Application |
20070270439 |
Kind Code |
A1 |
Chackalamannil; Samuel ; et
al. |
November 22, 2007 |
THROMBIN RECEPTOR ANTAGONISTS
Abstract
Heterocyclic-substituted tricyclics of the formula ##STR1## or a
pharmaceutically acceptable salt thereof, wherein: the dotted line
represents an optional single bond; represents an optional double
bond; n is 0-2; Q is cycloalkyl, optionally substituted by R.sup.13
and R.sup.14; R.sup.13 and R.sup.14 are independently selected from
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl, --OH,
(C.sub.1-C.sub.6)alkoxy, R.sup.27-aryl(C.sub.1-C.sub.6)alkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
halogen and haloalkyl; or R.sup.13 and R.sup.14 together form a
spirocyclic or a heterospirocyclic ring of 3-6 atoms; Het is a
mono- or bi-cyclic optionally substituted heteroaryl group; and B
is a bond, alkylene, or optionally substituted alkenylene or
alkynylene, wherein the remaining substituents are as defined in
the specification, are disclosed, as well as pharmaceutical
compositions containing them and a method of treating diseases
associated with thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, arrhythmia, heart failure, and
cancer by administering said compounds. Combination therapy with
other cardiovascular agents is also claimed.
Inventors: |
Chackalamannil; Samuel;
(Califon, NJ) ; Clasby; Martin C.; (Plainsboro,
NJ) ; Greenlee; William J.; (Teaneck, NJ) ;
Wang; Yuguang; (North Brunswick, NJ) ; Xia; Yan;
(Edison, NJ) ; Veltri; Enrico P.; (Princeton,
NJ) ; Chelliah; Mariappan V.; (Edison, NJ) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation
|
Family ID: |
29250954 |
Appl. No.: |
11/774358 |
Filed: |
July 6, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10412982 |
Apr 14, 2003 |
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11774358 |
Jul 6, 2007 |
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60373072 |
Apr 16, 2002 |
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Current U.S.
Class: |
514/256 ;
514/314; 514/333; 514/337; 544/333; 546/180; 546/256; 546/270.4;
546/284.1 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 9/12 20180101; A61P 25/00 20180101; A61P 43/00 20180101; C07D
405/06 20130101; A61P 7/02 20180101; A61P 9/06 20180101; A61P 13/12
20180101; A61P 9/10 20180101; A61P 9/00 20180101; A61P 9/02
20180101; C07D 405/14 20130101; A61P 9/04 20180101; A61P 7/00
20180101; A61P 35/00 20180101; A61P 29/00 20180101 |
Class at
Publication: |
514/256 ;
514/314; 514/333; 514/337; 544/333; 546/180; 546/256; 546/270.4;
546/284.1 |
International
Class: |
A61K 31/4427 20060101
A61K031/4427; A61K 31/506 20060101 A61K031/506; A61P 29/00 20060101
A61P029/00; A61P 35/00 20060101 A61P035/00; A61P 9/00 20060101
A61P009/00; A61P 9/02 20060101 A61P009/02; A61P 9/06 20060101
A61P009/06; A61P 9/10 20060101 A61P009/10; A61P 9/12 20060101
A61P009/12; C07D 221/00 20060101 C07D221/00; C07D 239/26 20060101
C07D239/26 |
Claims
1. A compound represented by the structural formula ##STR149## or a
pharmaceutically acceptable salt or solvate thereof, wherein: the
single dotted line represents an optional single bond; represents
an optional double bond; n is 0-2; Q is ##STR150## R.sup.1 is
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, fluoro(C.sub.1-C.sub.6)alkyl-,
difluoro(C.sub.1-C.sub.6)alkyl-, trifluoro-(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl,
hydroxy-(C.sub.1-C.sub.6)alkyl-, and amino(C.sub.1-C.sub.6)alkyl-;
R.sup.2 is independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, fluoro(C.sub.1-C.sub.6)alkyl-,
difluoro(C.sub.1-C.sub.6)alkyl-, trifluoro-(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.2-C.sub.6)alkenyl,
hydroxy-(C.sub.1-C.sub.6)alkyl-, and amino(C.sub.1-C.sub.6)alkyl-,
R.sup.3 is H, hydroxy, (C.sub.1-C.sub.6)alkoxy, --SOR.sup.16,
--SO.sub.2R.sup.17, --C(O)OR.sup.17, --C(O)NR.sup.18R.sup.19,
--(C.sub.1-C.sub.6)alkyl-C(O)NR.sup.18R.sup.19,
(C.sub.1-C.sub.6)alkyl, halogen, fluoro(C.sub.1-C.sub.6)alkyl-,
difluoro(C.sub.1-C.sub.6)alkyl-, trifluoro(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.6)alkyl-,
(C.sub.2-C.sub.6)alkenyl, aryl(C.sub.1-C.sub.6)alkyl-,
aryl(C.sub.2-C.sub.6)alkenyl-, heteroaryl(C.sub.1-C.sub.6)alkyl-,
heteroaryl(C.sub.2-C.sub.6)alkenyl-,
hydroxy(C.sub.1-C.sub.6)-alkyl-, --NR.sup.22R.sup.23,
NR.sup.22R.sup.23--(C.sub.1-C.sub.6)alkyl-, aryl,
thio(C.sub.1-C.sub.6)alkyl-,
(C.sub.1-C.sub.6)alkyl-thio(C.sub.1-C.sub.6)alkyl-,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-,
NR.sup.18R.sup.19--C(O)--(C.sub.1-C.sub.6)alkyl- or
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl-; Het is a mono-
or bi-cyclic heteroaryl group of 5 to 10 atoms comprised of 1 to 9
carbon atoms and 1 to 4 heteroatoms independently selected from the
group consisting of N, O and S, wherein a ring nitrogen can form an
N-oxide or a quaternary group with a (C.sub.1-C.sub.4)alkyl group,
wherein Het is attached to B by a carbon atom ring member, and
wherein the Het group is substituted by W; W is 1 to 4 substituents
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, fluoro(C.sub.1-C.sub.6)alkyl-,
difluoro(C.sub.1-C.sub.6)alkyl-, trifluoro(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl, hydroxy(C.sub.1-C.sub.6)alkyl-,
dihydroxy(C.sub.1-C.sub.6)alkyl-,
NR.sup.25R.sup.26(C.sub.1-C.sub.6)alkyl-,
thio(C.sub.1-C.sub.6)alkyl-, --OH, (C.sub.1-C.sub.6)alkoxy,
halogen, --NR.sup.4R.sup.5, --C(O)OR.sup.17, --COR.sup.16,
(C.sub.1-C.sub.6)alkylthio-, R.sup.21-aryl,
R.sup.21-aryl(C.sub.1-C.sub.6)alkyl-, aryl wherein adjacent carbons
form a ring comprising a methylenedioxy group, and
R.sup.21-heteroaryl; R.sup.4 and R.sup.5 are independently selected
from the group consisting of H, (C.sub.1-C.sub.6)alkyl, phenyl,
benzyl and (C.sub.3-C.sub.6)cycloalkyl, or R.sup.4 and R.sup.5
taken together are --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.2NR.sup.7--(CH.sub.2).sub.2-- and form a ring with
the nitrogen to which they are attached; R.sup.6 is H,
(C.sub.1-C.sub.6)alkyl or phenyl; R.sup.7 is H,
(C.sub.1-C.sub.6)alkyl, --C(O)--R.sup.16, --C(O)OR.sup.17 or
--SO.sub.2R.sup.17; R.sup.8, R.sup.10 and R.sup.11 are
independently selected from the group consisting of R.sup.1 and
--OR.sup.1, provided that when the optional double bond is present,
R.sup.10 is absent; R.sup.9 is H, OH or (C.sub.1-C.sub.6)alkoxy; B
is --(CH.sub.2).sub.n3--, cis or trans
--(CH.sub.2).sub.n4CR.sup.12.dbd.CR.sup.12a(CH.sub.2).sub.n5-- or
--(CH.sub.2).sub.n4C.ident.C(CH.sub.2).sub.n5--, wherein n.sub.3 is
0-5, n.sub.4 and n.sub.5 are independently 0-2, and R.sup.12 and
R.sup.12a are independently selected from the group consisting of
H, (C.sub.1-C.sub.6)alkyl and halogen; X is --O-- or --NR.sup.6--
when the dotted line represents a single bond, or X is --OH or
--NHR.sup.20 when the bond is absent; Y is .dbd.O, .dbd.S, (H, H),
(H, OH) or (H, (C.sub.1-C.sub.6)alkoxy) when the dotted line
represents a single bond, or when the bond is absent, Y is .dbd.O,
(H, H), (H, OH), (H, H) or (H, (C.sub.1-C.sub.6)alkoxy); each
R.sup.13 is independently selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4,
haloalkyl, and halogen; each R.sup.14 is independently selected
from H, (C.sub.1-C.sub.6)alkyl, --OH, (C.sub.1-C.sub.6)alkoxy,
R.sup.27-aryl(C.sub.1-C.sub.6)alkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, heterocyclylalkyl,
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4,
halogen and haloalkyl; or R.sup.13 and R.sup.14 taken together form
a spirocyclic or a heterospirocyclic ring of 3-6 atoms; wherein at
least one of R.sup.13 or R.sup.14 is selected from the group
consisting of --(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.6,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4;
R.sup.15 is absent when the dotted line represents a single bond
and is H, (C.sub.1-C.sub.6)alkyl, --NR.sup.18R.sup.19, or
--OR.sup.17 when the bond is absent; R.sup.16 is independently
selected from the group consisting of (C.sub.1-C.sub.6)alkyl,
phenyl and benzyl; R.sup.16b is H, alkoxy, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-,
R.sup.22--O--C(O)--(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl, R.sup.21-aryl,
R.sup.21aryl(C.sub.1-C.sub.6)alkyl, haloalkyl, alkenyl,
halosubstituted alkenyl, alkynyl, halosubstituted alkynyl,
R.sup.21-heteroaryl, R.sup.21-(C.sub.1-C.sub.6)alkyl heteroaryl,
R.sup.21-(C.sub.1-C.sub.6)alkyl heterocycloalkyl,
R.sup.28R.sup.29N--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--(CO)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--(CO)O--(C.sub.1-C.sub.6)alkyl,
R.sup.28O(CO)N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28S(O).sub.2N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--(CO)--N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--S(O)2N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28--(CO)N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--S(O).sub.2--(C.sub.1-C.sub.6)alkyl,
HOS(O).sub.2--(C.sub.1-C.sub.6)alkyl,
(OH).sub.2P(O).sub.2--(C.sub.1-C.sub.6)alkyl,
R.sup.28--S--(C.sub.1-C.sub.6)alkyl,
R.sup.28--S(O).sub.2--(C.sub.1-C.sub.6)alkyl or
hydroxy(C.sub.1-C.sub.6)alkyl); R.sup.17, R.sup.18 and R.sup.19 are
independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, phenyl, and benzyl; R.sup.20 is H,
(C.sub.1-C.sub.6)alkyl, phenyl, benzyl, --C(O)R.sup.6 or
--SO.sub.2R.sup.6; R.sup.21 is 1 to 3 substituents independently
selected from the group consisting of H, --CN, --CF.sub.3,
--OCF.sub.3, halogen, --NO.sub.2, (C.sub.1-C.sub.6)alkyl, --OH,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)-alkylamino-,
di-((C.sub.1-C.sub.6)alkyl)amino-,
NR.sup.25R.sup.26--(C.sub.1-C.sub.6)alkyl-,
hydroxy-(C.sub.1-C.sub.6)alkyl-, --C(O)OR.sup.17, --C(O)R.sup.17,
--NHCOR.sup.16, --NHSO.sub.2R.sup.16, --NHSO.sub.2CH.sub.2CF.sub.3,
--C(O)NR.sup.25R.sup.26, --NR.sup.25--C(O)--NR.sup.25R.sup.26,
--S(O)R.sup.13, --S(O)R.sup.13 and --SR.sup.13; R.sup.22 is H or
(C.sub.1-C.sub.6)alkyl; R.sup.23 is H, (C.sub.1-C.sub.6)alkyl,
--C(O)R.sup.24, --SO.sub.2R.sup.24, --C(O)NHR.sup.24 or
--SO.sub.2NHR.sup.24; R.sup.24 is (C.sub.1-C.sub.6)alkyl, hydroxy
(C.sub.1-C.sub.6)alkyl or
NR.sup.25R.sup.26--((C.sub.1-C.sub.6)alkyl-; R.sup.25 and R.sup.26
are independently selected from the group consisting of H and
(C.sub.1-C.sub.6)alkyl; R.sup.27 is 1, 2 or 3 substituents selected
from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, halogen and
--OH; and R.sup.28 and R.sup.29 are independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, R.sup.27-aryl(C.sub.1-C.sub.6)alkyl,
heteroaryl, heteroarylalkyl, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, heterocyclyl,
heterocyclylalkyl, and haloalkyl; or R.sup.28 and R.sup.29 taken
together form a spirocyclic or a heterospirocyclic ring of 3-6
atoms.
2. A compound of claim 1 wherein n is 0.
3. A compound of claim 1 wherein the optional double bond is not
present.
4. A compound of claim 1 wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H and
(C.sub.1-C.sub.6)alkyl.
5. A compound of claim 4 wherein R.sup.1 is (C.sub.1-C.sub.6)alkyl
and R.sup.2 is H.
6. A compound of claim 1 wherein R.sup.3 is H, --OH,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, halogen,
(C.sub.3-C.sub.6)cycloalkyl, --C(O)OR.sup.17 or
--NR.sup.22R.sup.23.
7. A compound of claim 6 wherein R.sup.3 is H or
(C.sub.1-C.sub.6)alkyl.
8. A compound of claim 1 wherein Het is pyridyl attached to B by a
carbon ring member, and is substituted by 1 or 2 substituents
selected from W.
9. A compound of claim 8 wherein W is R.sup.21-phenyl or
R.sup.21-pyridyl.
10. A compound of claim 1 wherein R.sup.8, R.sup.10 and R.sup.11
are each independently selected from the group consisting of H and
(C.sub.1-C.sub.6)alkyl and R.sup.9 is H.
11. A compound of claim 1 wherein B is CH.dbd.CH--.
12. A compound of claim 1 wherein the optional single bond is
present, X is --O--, Y is .dbd.O, and R.sup.15 is absent.
13. A compound of claim 1 wherein Q is ##STR151## wherein at least
one of R.sup.13 and R.sup.14 is R.
14. A compound of claim 13 wherein Q is ##STR152##
15. A compound of claim 1 wherein R is
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHCOR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16 or
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5; R.sup.16b, R.sup.16
and R.sup.4 are (C.sub.1-C.sub.6)alkyl; and R.sup.5 is H, where
n.sub.6 is 0-4.
16. A compound of claim 15 wherein R is --NHC(O)OR.sup.16b,
--NHC(O)R.sup.16b or --NHC(O)NR.sup.4R.sup.5, R.sup.16b and R.sup.4
are (C.sub.1-C.sub.6)alkyl, and R.sup.5 is H.
17. A compound of claim 16 wherein R is --NHC(O)OR.sup.16b wherein
R.sup.16b is (C.sub.1-C.sub.6)alkyl.
18. A compound of claim 1 wherein n is 0, the optional single bond
is present, X is --O--, Y is .dbd.O and R.sup.15 is absent.
19. A compound of claim 18 wherein R.sup.2, R.sup.3, R.sup.8,
R.sup.9, R.sup.10 and R.sup.11 are each hydrogen, R.sup.1 is
--CH.sub.3, B is --CH.dbd.CH--, Het is W-pyridyl, W is
R.sup.21-phenyl or R.sup.21-pyridyl, and R.sup.21 is --CF.sub.3 or
F.
20. A compound of claim 19 wherein R is --NHC(O)OR.sup.16b and
R.sup.16b is --CH.sub.3 or --CH.sub.2CH.sub.3.
21. A compound of claim 1 selected from the group consisting of
##STR153## ##STR154## ##STR155## ##STR156## ##STR157##
22. The compound of claim 1 wherein said salt is a bisulfate.
23. A pharmaceutical composition comprising an effective amount of
a compound of claim 1 and a pharmaceutically acceptable
carrier.
24. A method of inhibiting thrombin receptors comprising
administering to a mammal in need of such treatment an effective
amount of a compound of claim 1.
25. A method of treating thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, arrhythmia, heart failure,
myocardial infarction, glomerulonephritis, thrombotic stroke,
thromboembolic stroke, peripheral vascular diseases, inflammatory
disorders, cerebral ischemia or cancer, comprising administering to
a mammal in need of such treatment an effective amount of a
compound of claim 1.
26. A method of treating thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, arrhythmia, heart failure,
myocardial infarction, glomerulonephritis, thrombotic stroke,
thromboembolytic stroke, peripheral vascular diseases, inflammatory
disorders, cerebral ischemia or cancer, comprising administering to
a mammal in need of such treatment an effective amount of a
compound of claim 1 in combination with an additional
cardiovascular agent.
27. The method of claim 26 wherein the additional cardiovascular
agent is selected from the group consisting of thromboxane A2
biosynthesis inhibitors, GP IIb/IIIa antagonists, thromboxane
antagonists, adenosine diphosphate inhibitors, cyclooxygenase
inhibitors, angiotensin antagonists, endothelin antagonists,
angiotensin converting enzyme inhibitors, neutral endopeptidase
inhibitors, anticoagulants, diuretics, and platelet aggregation
inhibitors.
28. The method of claim 27 wherein the additional cardiovascular
agent is aspirin or clopidogrel bisulfate.
Description
[0001] The present application claims priority under 35 USC section
119(e) of U.S. Provisional application Ser. No. 60/373,072, filed
Apr. 16, 2002, the complete text, claims and figures of which are
incorporated by reference herein as if fully set forth.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to substituted tricyclic
thrombin receptor antagonists, pharmaceutical compositions
containing them and their use in the treatment of diseases
associated with thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, arrhythmia, heart failure, cerebral
ischemia, stroke, inflammatory disorders, neurodegenerative
diseases and cancer. The invention also relates to the combination
of novel compounds of the invention and other cardiovascular
agents.
[0003] Thrombin is known to have a variety of activities in
different cell types and thrombin receptors are known to be present
in such cell types as human platelets, vascular smooth muscle
cells, endothelial cells and fibroblasts. It is therefore possible
that thrombin receptor antagonists, also known as protease
activated receptor (PAR) antagonists will be useful in the
treatment of thrombotic, inflammatory, atherosclerotic and
fibroproliferative disorders, as well as other disorders in which
thrombin and its receptor play a pathological role.
[0004] Thrombin receptor antagonists peptides have been identified
based on structure-activity studies involving substitutions of
amino acids on thrombin receptors. In Bernatowicz et al, J. Med.
Chem., vol. 39, pp. 4879-4887 (1996), tetra- and pentapeptides are
disclosed as being potent thrombin receptor antagonists, for
example
N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH.sub.2 and
N-trans-cinnamoyl-p-fluoroPhe-pguanidinoPhe-Leu-Arg-Arg-NH.sub.2.
Peptide thrombin receptor antagonists are also disclosed in WO
94103479, published Feb. 17, 1994.
[0005] Substituted tricyclic thrombin receptor antagonists are
disclosed in U.S. Pat. No. 6,063,847, U.S. Pat. No. 6,326,380 and
U.S. Ser. Nos. 09/880,222 (WO 01/96330) and 10/271,715.
SUMMARY OF THE INVENTION
[0006] The present invention relates to thrombin receptor
antagonists represented by the Formula I: ##STR2## or a
pharmaceutically acceptable salt or solvate thereof, wherein:
[0007] the single dotted line represents an optional single bond;
[0008] represents an optional double bond; [0009] n is 0-2; [0010]
Q is ##STR3## [0011] R.sup.1 is independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl,
fluoro(C.sub.1-C.sub.6)alkyl-, difluoro(C.sub.1-C.sub.6)alkyl-,
trifluoro-(C.sub.1-C.sub.6)alkyl-, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.2-C.sub.6) alkenyl, hydroxy-(C.sub.1-C.sub.6)alkyl-, and
amino(C.sub.1-C.sub.6)alkyl-; [0012] R.sup.2 is independently
selected from the group consisting of H, (C.sub.1-C.sub.6)alkyl,
fluoro(C.sub.1-C.sub.6)alkyl-, difluoro(C.sub.1-C.sub.6)alkyl-,
trifluoro-(C.sub.1-C.sub.6)alkyl-, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.2-C.sub.6)alkenyl, hydroxy-(C.sub.1-C.sub.6)alkyl-, and
amino(C.sub.1-C.sub.6)alkyl-; [0013] R.sup.3 is H, hydroxy,
(C.sub.1-C.sub.6)alkoxy, --SOR.sup.16, --SO.sub.2R.sup.17,
--C(O)OR.sup.17,
--C(O)NR.sup.18R.sup.19-(C.sub.1-C.sub.6)alkyl-C(O)NR.sup.18R.sup.19,
(C.sub.1-C.sub.6)alkyl, halogen, fluoro(C.sub.1-C.sub.6)alkyl-,
difluoro(C.sub.1-C.sub.6)alkyl-, trifluoro(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl,
(C.sub.3-C.sub.6)-cycloalkyl-(C.sub.1-C.sub.6)alkyl-,
(C.sub.2-C.sub.6)alkenyl, aryl(C.sub.1-C.sub.6)alkyl-,
aryl(C.sub.2-C.sub.6)alkenyl-, heteroaryl(C.sub.1-C.sub.6)alkyl-,
heteroaryl(C.sub.2-C.sub.6)alkenyl-,
hydroxy(C.sub.1l-C.sub.6)alkyl-, --NR.sup.22R.sup.23 ,
NR.sup.2R.sup.23(C.sub.1-C.sub.6)alkyl-, aryl,
thio(C.sub.1-C.sub.6)alkyl-,
(C.sub.1-C.sub.6)alkyl-thio(C.sub.1-C.sub.6)alkyl-,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-,
NR.sup.18R.sup.19--C(O)--(C.sub.1-C.sub.6)alkyl- or
(C.sub.3-C.sub.6)cycloalkyl-(C.sub.1-C.sub.6)alkyl-; [0014] Het is
a mono- or bi-cyclic heteroaryl group of 5 to 10 atoms comprised of
1 to 9 carbon atoms and 1 to 4 heteroatoms independently selected
from the group consisting of N, O and S, wherein a ring nitrogen
can form an N-oxide or a quaternary group with a C.sub.1-C.sub.4
alkyl group, wherein Het is attached to B by a carbon atom ring
member, and wherein the Het group is substituted by W; [0015] W is
1 to 4 substituents independently selected from the group
consisting of H, (C.sub.1-C.sub.6)alkyl,
fluoro(C.sub.1-C.sub.6)alkyl-, difluoro(C.sub.1-C.sub.6)alkyl-,
trifluoro(C.sub.1-C.sub.6)alkyl-, (C.sub.3-C.sub.6)cycloalkyl,
hydroxy(C.sub.1-C.sub.6)alkyl-, dihydroxy(C.sub.1-C.sub.6)alkyl-,
NR.sup.25R.sup.26(C.sub.1-C.sub.6)alkyl-,
thio(C.sub.1-C.sub.6)alkyl-, -OH, (C.sub.1-C.sub.6)alkoxy, halogen,
--NR.sup.4R.sup.5, --C(O)OR.sup.17, --C(O)R.sup.16,
(C.sub.1-C.sub.6)alkylthio, R.sup.21-aryl,
R.sup.21-aryl(C.sub.1-C.sub.6)alkyl-, aryl wherein adjacent carbons
form a ring comprising a methylenedioxy group, and
R.sup.21-heteroaryl;
[0016] R.sup.4 and R.sup.5 are independently selected from the
group consisting of H, (C.sub.1-C.sub.6)alkyl, phenyl, benzyl and
(C.sub.3-C.sub.6)cycloalkyl, or R.sup.4 and R.sup.5 taken together
are --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5-- or
--(CH.sub.2).sub.2NR.sup.7--(CH.sub.2).sub.2-- and form a ring with
the nitrogen to which they are attached; [0017] R.sup.6 is H,
(C.sub.1-C.sub.6)alkyl or phenyl; [0018] R.sup.7 is H,
(C.sub.1-C.sub.6)alkyl, --C(O--R.sup.16, --C(O)OR.sup.17 or
--SO.sub.2R.sup.17; [0019] R.sup.8, R.sup.10 and R.sup.11 are
independently selected from the group consisting of R.sup.1 and
--OR.sup.1, provided that when the optional double bond is present,
R.sup.10 is absent; [0020] R.sup.9 is H, OH or
(C.sub.1-C.sub.6)alkoxy; [0021] B is --(CH.sub.2).sub.n3--, cis or
trans --(CH.sub.2).sub.n4CR.sup.12.dbd.CR.sup.12a(CH.sub.2).sub.n5
or --(CH.sub.2).sub.n4C.ident.C(CH.sub.2).sub.n5--, wherein n.sub.3
is 0-5, n.sub.4 and n.sub.5 are independently 0-2, and R.sup.12 and
R.sup.12a are independently selected from the group consisting of
H, (C.sub.1-C.sub.6)alkyl and halogen; [0022] X is --O-- or
--NR.sup.6-- when the dotted line represents a single bond, or X is
--OH or --NHR.sup.20 when the bond is absent; [0023] Y is .dbd.O,
.dbd.S, (H, H), (H, OH) or (H, (C.sub.1-C.sub.6)alkoxy) when the
dotted line represents a single bond, or when the bond is absent, Y
is .dbd.O, (H, H), (H, OH), (H, SH) or (H,
(C.sub.1-C.sub.6)alkoxy); [0024] each R.sup.13 is independently
selected from H, (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, --(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4,
haloalkyl, and halogen; [0025] each R.sup.14 is independently
selected from H, (C.sub.1-C.sub.6)alkyl, --OH,
(C.sub.1-C.sub.6)alkoxy, R.sup.27-aryl(C.sub.1-C.sub.6)alkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl,
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4,
halogen and haloalkyl; or [0026] R.sup.13 and R.sup.14 taken
together form a spirocyclic or a heterospirocyclic ring of 3-6
atoms; [0027] wherein at least one of R.sup.13 or R.sup.14 is
selected from the group consisting of
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16,
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5, and
--(CH.sub.2).sub.n6C(O)NR.sup.28R.sup.29 where n.sub.6 is 0-4;
[0028] R.sup.15 is absent when the dotted line represents a single
bond and is H. (C.sub.1-C.sub.6)alkyl, --NR.sup.18R.sup.19, or
--OR.sup.17 when the bond is absent; [0029] R.sup.16 is
independently selected from the group consisting of
(C.sub.1-C.sub.6)alkyl, phenyl and benzyl; [0030] R.sup.16b is H,
alkoxy, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-,
R.sup.22--C(O)--(C.sub.1-C.sub.6)alkyl-,
(C.sub.3-C.sub.6)cycloalkyl, R.sup.21-aryl,
R.sup.21-aryl(C.sub.1-C.sub.6)alkyl, haloalkyl, alkenyl,
halosubstituted alkenyl, alkynyl, halosubstituted alkynyl,
R.sup.21-heteroaryl, R.sup.21--(C.sub.1-C.sub.6)alkyl heteroaryl,
R.sup.21--(C.sub.1-C.sub.6)alkyl heterocycloalkyl,
R.sup.28R.sup.29N--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--(CO)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--(CO)O--(C.sub.1-C.sub.6)alkyl,
R.sup.28O(CO)N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28S(O).sub.2N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--(CO)--N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--S(O)2N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28--(CO)N(R.sup.29)--(C.sub.1-C.sub.6)alkyl,
R.sup.28R.sup.29N--S(O).sub.2--(C.sub.1-C.sub.6)alkyl,
HOS(O).sub.2--(C.sub.1-C.sub.6)alkyl,
(OH).sub.2P(O).sub.2--(C.sub.1-C.sub.6)alkyl,
R.sup.28--S--(C.sub.1-C.sub.6)alkyl,
R.sup.28-S(O).sub.2(C.sub.1-C.sub.6)alkyl or
hydroxy(C.sub.1-C.sub.6)alkyl); [0031] R.sup.17, R.sup.18 and
R.sup.19 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, phenyl, and benzyl; [0032] R.sup.20 is H,
(C.sub.1-C.sub.6)alkyl, phenyl, benzyl, --C(O)R.sup.6 or
--SO.sub.2R.sup.6; [0033] R.sup.21 is 1 to 3 substituents
independently selected from the group consisting of H, --CN,
--CF.sub.3, --OCF.sub.3, halogen, --NO.sub.2,
(C.sub.1-C.sub.6)alkyl, --OH, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylamino-, di-((C.sub.1-C.sub.6)alkyl)amino-,
NR.sup.25R.sup.26(C.sub.1-C.sub.6)alkyl-,
hydroxy-(C.sub.1-C.sub.6)alkyl-, --C(O)OR.sup.17, --COR.sup.17,
--NHCOR.sup.16, --NHSO.sub.2R.sup.16, --NHSO.sub.2CH.sub.2CF.sub.3,
--C(O)NR.sup.25R.sup.26, --NR.sup.25--C(O)--NR.sup.25R.sup.26,
--S(O)R.sup.13, --S(O).sub.2R.sup.13 and --SR.sup.13; [0034]
R.sup.22 is H or (C.sub.1-C.sub.6)alkyl; [0035] R.sup.23 is H,
(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.24, --SO.sub.2R.sup.24,
--CONHR.sup.24 or --SO.sub.2NHR.sup.24; [0036] R.sup.24 is
(C.sub.1-C.sub.6)alkyl, hydroxy (C.sub.1-C.sub.6)alkyl or
NR.sup.25R.sup.26--((C.sub.1-C.sub.6)alkyl)-; [0037] R.sup.25 and
R.sup.26 are independently selected from the group consisting of H
and (C.sub.1-C.sub.6)alkyl; [0038] R.sup.27 is 1, 2 or 3
substituents selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
(C.sub.1-C.sub.6)alkoxy, halogen and --OH; and [0039] R.sup.28 and
R.sup.29 are independently selected from the group consisting of H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
R.sup.27-aryl(C.sub.1-C.sub.6)alkyl, heteroaryl, heteroarylalkyl,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, heterocyclyl,
heterocyclylalkyl, and haloalkyl; or [0040] R.sup.28 and R.sup.2
taken together form a spirocyclic or a heterospirocyclic ring of
3-6 atoms.
[0041] Thrombin receptor antagonist compounds of the present
invention can have anti-thrombotic, anti-platelet aggregation,
antiatherosclerotic, antirestenotic and/or anti-coagulant activity.
Thrombosis-related diseases treated by the compounds of this
invention include thrombosis, atherosclerosis, restenosis,
hypertension, angina pectoris, arrhythmia, heart failure,
myocardial infarction, glomerulonephritis, thrombotic and
thromboembolytic stroke, peripheral vascular diseases, other
cardiovascular diseases, cerebral ischemia, inflammatory disorders
and cancer, as well as other disorders in which thrombin and its
receptor play a pathological role.
[0042] Certain embodiments of this invention also relate to a
method of using at least one compound of Formula I in combination
with one or more additional cardiovascular agents for the treatment
of thrombosis, platelet aggregation, coagulation, cancer,
inflammatory diseases or respiratory diseases, comprising
administering a combination of at least one compound of formula I
and at least one additional cardiovascular agent to a mammal in
need of such treatment. In particular, the present invention
relates to a method of using said combination in the treatment of
thrombosis, atherosclerosis, restenosis, hypertension, angina
pectoris, arrhythmia, heart failure, myocardial infarction,
glomerulonephritis, thrombotic stroke, thromboembolic stroke,
peripheral vascular diseases, cerebral ischemia, cancer, rheumatoid
arthritis, systemic lupus erythematosus, multiple sclerosis,
diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral
ischemia, nephritis, inflammatory disorders of the lungs and
gastrointestinal tract, reversible airway obstruction, chronic
asthma or bronchitis. It is contemplated that a combination of this
invention may be useful in treating more than one of the diseases
listed.
[0043] Some embodiments of the invention relate to a pharmaceutical
composition comprising a therapeutically effective amount of a
combination of at least one compound of formula I and at least one
additional cardiovascular agent in a pharmaceutically acceptable
carrier.
[0044] Some embodiments of the invention relate to the use of a
thrombin receptor antagonist disclosed in any of U.S. Pat. No.
6,063,847, U.S. Pat. No. 6,326,380, U.S. Ser. Nos. 09/880,222 and
10/271,715, all of which are incorporated herein by reference, in
combination with one or more additional cardiovascular agents, for
the treatment of thrombosis, platelet aggregation, coagulation,
cancer, inflammatory diseases or respiratory diseases. In
particular, the present invention relates to a method of using said
combination in the treatment of thrombosis, atherosclerosis,
restenosis, hypertension, angina pectoris, arrhythmia, heart
failure, myocardial infarction, glomerulonephritis, thrombotic
stroke, thromboembolic stroke, peripheral vascular diseases,
cerebral ischemia, cancer, rheumatoid arthritis, systemic lupus
erythematosus, multiple sclerosis, diabetes, osteoporosis, renal
ischemia, cerebral stroke, cerebral ischemia, nephritis,
inflammatory disorders of the lungs and gastrointestinal tract,
reversible airway obstruction, chronic asthma or bronchitis.
[0045] It is further contemplated that the combination of the
invention can be provided as a kit comprising in a single package
at least one compound of formula I in a pharmaceutical composition,
and at least one separate pharmaceutical composition comprising a
cardiovascular agent.
DETAILED DESCRIPTION
[0046] For compounds of Formula I, preferred definitions of the
variables are as follows:
[0047] The variable n is preferably 0-2, and more preferably 0. The
optional double bond is preferably absent (i.e., the bond is a
single bond).
[0048] Q is preferably: ##STR4## with the six-membered Q ring being
more preferred R.sup.13 is preferably H or CH.sub.3. R.sup.14 is
preferably H or --CH.sub.3. For the five-membered Q ring,
preferably no more than two R.sup.13 and R.sup.14 substituents are
other than hydrogen. For the six-membered Q ring, preferably no
more than four R.sup.13 and R.sup.14 substituents are other than
hydrogen, more preferably no more than two R.sup.13 and R.sup.14
substituents are other than hydrogen.
[0049] Especially preferred Q rings are: ##STR5## preferably shown
as ##STR6## respectively.
[0050] In the preferred Q rings above, R is preferably
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHC(O)R.sup.16b,
--(CH.sub.2).sub.n6NHC(O)NR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16 or
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5 wherein n.sub.6 is
0-2, and R.sup.16b, R.sup.16 and R.sup.4 are (C.sub.1-C.sub.6)alkyl
and R.sup.5 is H. More preferred are compounds of Formula I wherein
R is --NHC(O)OR.sup.16b, --NHC(O)R.sup.16b,
--NHC(O)NR.sup.4R.sup.5, --NHSO.sub.2R.sup.16 or
--NHSO.sub.2NR.sup.4R.sup.5 wherein R.sup.16b, R.sup.16 and R.sup.4
are (C.sub.1-C.sub.6)alkyl and R.sup.5 is H. Even more preferred
are compounds of Formula I wherein R is --NHC(O)OR.sup.16b,
--NHC(O)R.sup.16b or --NHC(O)NR.sup.4R.sup.5, wherein R.sup.16b and
R.sup.4 are (C.sub.1-C.sub.6)alkyl and R.sup.5 is H. [0051] R.sup.1
and R.sup.2 are preferably independently selected from the group
consisting of H and (C.sub.1-C.sub.6)alkyl; more preferably,
R.sup.1 is (C.sub.1-C.sub.6)alkyl and R.sup.2 is H; especially
preferred are compounds wherein R.sup.1 is --CH.sub.3 and R.sup.2
is H.
[0052] R.sup.3 is preferably H, --OH, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, halogen, (C.sub.3-C.sub.6)cycloalkyl,
--C(O)OR.sup.17 or --NR.sup.22R.sup.23; more preferably, R.sup.3 is
H or (C.sub.1-C.sub.6)alkyl.
[0053] Het is preferably pyridyl attached to B by a carbon ring
member, and is preferably substituted by 1 or 2 substituents
selected from W, more preferably 1 substituent. W is preferably
R.sup.21-aryl or R.sup.21-heteroaryl. Aryl is preferably phenyl.
Heteroaryl is preferably pyridyl. R.sup.21 is preferably H, halogen
or --CN, or --CF.sub.3, especially F, --CN or --CF.sub.3. [0054]
R.sup.8, R.sup.10 and R.sup.11 are each independently preferably H
or (C.sub.1-C.sub.6)alkyl, more preferably H or --CH.sub.3;
especially preferred are compounds of Formula I wherein R.sup.8,
R.sup.10 and R.sup.11 are each H. [0055] R.sup.9 is preferably H,
OH or (C.sub.1-C.sub.6)alkoxy; more preferably, R.sup.9 is H.
[0056] B is preferably cis or trans
--(CH.sub.2).sub.4CR.sup.12.dbd.CR.sup.12a(CH.sub.2).sub.n5--
wherein n.sub.4, n.sub.5, R.sup.12 and R.sup.12a are as defined
above; more preferably, R.sup.12 and R.sup.12a are each H, and
n.sub.4 and n.sub.5 are each zero. Particularly preferred are
compounds wherein B is trans-alkenyl, especially --CH.dbd.CH--.
[0057] One group of preferred compounds is that wherein the
optional single bond is present, X is --O--, Y is .dbd.O, and
R.sup.15 is absent. Another preferred group of compounds is that
wherein the optional single bond is absent, X is --OH, Y is (H,OH)
and R.sup.15 is H. Compounds wherein the optional single bond is
present, X is --O--, Y is .dbd.O, and R.sup.15 is absent are more
preferred. [0058] Especially preferred are compounds of Formula I
wherein R is --HC(O)OR.sup.16b wherein R.sup.16b is
(C.sub.1-C.sub.6)alkyl. R.sup.16b is preferably methyl or ethyl.
Also preferred are compounds wherein the R group is attached to the
C-7 position of the Q ring, as shown in Formula IA below.
[0059] A preferred embodiment of the invention is a compound of
Formula IA: ##STR7## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.8,
R.sup.10, R.sup.11, B, and Het are defined as preferred above. At
least one of ring carbon atoms 5-8 is preferably substituted with
--(CH.sub.2).sub.n6NHC(O)OR.sup.16b,
--(CH.sub.2).sub.n6NHCOR.sup.16b,
--(CH.sub.2).sub.n6NHCONR.sup.4R.sup.5,
--(CH.sub.2).sub.n6NHSO.sub.2R.sup.16 or
--(CH.sub.2).sub.n6NHSO.sub.2NR.sup.4R.sup.5 wherein n.sub.6 is
0-2, and R.sup.16b, R.sup.16 and R.sup.4 are (C.sub.1-C.sub.6)alkyl
and R.sup.5 is H.
[0060] A more preferred embodiment of the invention is a compound
of Formula IB: ##STR8## wherein Het is pyridyl substituted by an
R.sup.21-aryl group, preferably an R.sup.21-phenyl group wherein
R.sup.21 is preferably F or --CF.sub.3.
[0061] Especially preferred are compounds of Formula IA or 1B
wherein at least one of ring carbon atoms 5-8 is --NHC(O)OR.sup.16b
wherein R.sup.16b is (C.sub.1-C.sub.6)alkyl. R.sup.16b is
preferably methyl or ethyl.
[0062] As used above, and throughout the specification, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings: [0063] "Subject" includes both mammals
and non-mammalian animals. [0064] "Mammal" includes humans and
other mammalian animals.
[0065] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties. It
should be noted that any atom with unsatisfied valences in the
text, schemes, examples and tables herein is assumed to have the
hydrogen atom(s) to satisfy the valences.
[0066] The following definitions apply regardless of whether a term
is used by itself or in combination with other terms, unless
otherwise indicated. Therefore, the definition of "alkyl" applies
to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl",
"haloalkyl", "alkoxy", etc.
[0067] As used herein, the term "alkyl" means an aliphatic
hydrocarbon group that can be straight or branched and comprises 1
to about 20 carbon atoms in the chain. Preferred alkyl groups
comprise 1 to about 12 carbon atoms in the chain. More preferred
alkyl groups comprise 1 to about 6 carbon atoms in the chain.
"Branched" means that one or more lower alkyl groups such as
methyl, ethyl or propyl, are attached to a linear alkyl chain. The
alkyl can be substituted by one or more substituents independently
selected from the group consisting of halo, aryl, cycloalkyl,
cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2 (which alkyls can be the same or
different), carboxy and --C(O)O-alkyl. Non-limiting examples of
suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl,
trifluoromethyl and cyclopropylmethyl.
[0068] "Alkenyl" means an aliphatic hydrocarbon group (straight or
branched carbon chain) comprising one or more double bonds in the
chain and which can be conjugated or unconjugated. Useful alkenyl
groups can comprise 2 to about 15 carbon atoms in the chain,
preferably 2 to about 12 carbon atoms in the chain, and more
preferably 2 to about 6 carbon atoms in the chain. The alkenyl
group can be substituted by one or more substituents independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano and alkoxy. Non-limiting examples of suitable
alkenyl groups include ethenyl, propenyl, n-butenyl,
3-methylbut-enyl and n-pentenyl.
[0069] Where an alkyl or alkenyl chain joins two other variables
and is therefore bivalent, the terms alkylene and alkenylene,
respectively, are used.
[0070] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Useful alkoxy groups can comprise 1 to
about 12 carbon atoms, preferably 1 to about 6 carbon atoms.
Non-limiting examples of suitable alkoxy groups include methoxy,
ethoxy and isopropoxy. The alkyl group of the alkoxy is linked to
an adjacent moiety through the ether oxygen.
[0071] "Alkynyl" means an aliphatic hydrocarbon group comprising at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. Non-limiting examples of suitable alkynyl groups
include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl,
and decynyl. The alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0072] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 5 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl can be substituted with
one or more substituents, as defined above, which may be the same
or different. Non-limiting examples of suitable aryl groups include
phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.
"Arylene" means a bivalent phenyl group, including ortho, meta and
para-substitution.
[0073] The term "Boc" refers to N-tert-butoxycarbonyl.
[0074] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
substituted with one or more substituents, as defined above, which
may be the same or different. Non-limiting examples of suitable
monocyclic cycloalkyls include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and the like. Non-limiting examples of
suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl,
adamantyl and the like. "Cycloalkylene" refers to a corresponding
bivalent ring, wherein the points of attachment to other groups
include all positional isomers.
[0075] "Dihydroxy(C.sub.1-C.sub.6)alkyl" refers to an alkyl chain
substituted by two hydroxy groups on two different carbon
atoms.
[0076] "Fluoroalkyl", "difluoroalkyl" and "trifluoroalkyl" mean
alkyl chains wherein the terminal carbon is substituted by 1, 2 or
3 fluoroatoms, respectively, e.g., --CF.sub.3, --CH.sub.2CF.sub.3 ,
--CH.sub.2CHF.sub.2 or --CH.sub.2CH.sub.2F.
[0077] "Halogen" or "halo" refers to fluorine, chlorine, bromine or
iodine radicals. Preferred are fluoro, chloro or bromo, and more
preferred are fluoro and chloro.
[0078] "Heteroaryl" means a single ring, bicyclic or benzofused
heteroaryl group of 5 to 14 ring atoms, preferably about 5 to 10
ring atoms, comprised of 1 to 13 carbon atoms and 1 to 4
heteroatoms independently selected from the group consisting of N,
O and S, provided that the rings do not include adjacent oxygen
and/or sulfur atoms. N-oxides of the ring nitrogens are also
included, as well as compounds wherein a ring nitrogen is
substituted by a (C.sub.1-C.sub.4)alkyl group to form a quaternary
amine. Examples of single-ring heteroaryl groups are pyridyl,
oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl,
imidazolyl, pyrazolyl, tetrazolyl, thiazolyli isothiazolyl,
thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl.
Examples of bicyclic heteroaryl groups are naphthyridyl (e.g., 1, 5
or 1, 7), imidazopyridyl, pyrdo[2,3]imidazolyl, pyridopyrimidinyl
and 7-azaindolyl. Examples of benzofused heteroaryl groups are
indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e.,
thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyl and
benzofurazanyl. All positional isomers are contemplated, e.g.,
2-pyridyl, 3-pyridyl and 4-pyridyl.
[0079] The term "Het" is exemplified by the single ring, bicyclic
and benzofused heteroaryl groups as defined immediately above. Het
groups are joined to group B by a carbon ring member, e.g., Het is
2-pyridyl, 3-pyridyl or 2-quinolyl. The Het ring can be substituted
on any available ring carbon by a group W; 1 to 4 W substituents
can be present on a Het ring.
[0080] "Heterocycloalkyl" means a 4 to 6 membered saturated ring
containing 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from
the group consisting of N, S and O, provided that the heteroatoms
are not adjacent. Examples of heterocycloalkyl rings are
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,
tetrahydrofuranyl, tetrahydrothiophenyl and
tetrahydrothiopyranyl.
[0081] The term "heterospirocyclic" refers to a spirocyclic
structure containing 3 to 5 carbon atoms and 1 or 2 heteroatoms
selected from the group consisting of N, S and O, provided that the
heteroatoms are not adjacent.
[0082] The term "optional single bond" refers to the bond shown by
the dotted line between X and the carbon to which Y and R.sup.15
are attached in the structure of Formula I. The optional double
bond represented by means that at least a single bond must be
present, but that a double bond can be present, when the double
bond is present, R.sup.10 is absent.
[0083] When R.sup.4 and R.sup.5 join to form a ring with the
nitrogen to which they are attached, the rings formed are
1-pyrrolidinyl, 1-piperidinyl and 1-piperazinyl, wherein the
piperazinyl ring may also be substituted at the 4-position nitrogen
by a group R.sup.7.
[0084] The above statements, wherein, for example, R.sup.4 and
R.sup.5 are said to be independently selected from a group of
substituents, means that R.sup.4 and R.sup.5 are independently
selected when attached to the same nitrogen, but also that where an
R.sup.4 or R.sup.5 variable occurs more than once in a molecule,
those occurrences are independently selected. Similarly, each
occurrence of R.sup.13 or R.sup.14 is independent of any other
R.sup.13 or R.sup.14 in the same Q ring. Those skilled in the art
will recognize that the size and nature of the substituent(s) will
affect the number of substituents which can be present.
[0085] Compounds of the invention have at least one asymmetrical
carbon atom and therefore all isomers, including enantiomers,
stereoisomers, rotamers, tautomers and racemates of the compounds
of Formula (I) (where they exist) are contemplated as being part of
this invention. The invention includes d and I isomers in both pure
form and in admixture, including racemic mixtures. Isomers can be
prepared using conventional techniques, either by reacting
optically pure or optically enriched starting materials or by
separating isomers of a compound of Formula I. Isomers may also
include geometric isomers, e.g., when a double bond is present.
Polymorphous forms of the compounds of Formula (I), whether
crystalline or amorphous, also are contemplated as being part of
this invention.
[0086] Those skilled in the art will appreciate that for some of
the compounds of Formula I, one isomer will show greater
pharmacological activity than other isomers.
[0087] Typical preferred compounds of the present invention have
the following stereochemistry: ##STR9## with compounds having that
absolute stereochemistry being more preferred.
[0088] Those skilled in the art will appreciate that for some
compounds of Formula I, one isomer will show greater
pharmacological activity than other isomers.
[0089] Compounds of the invention with a basic group can form
pharmaceutically acceptable salts with organic and inorganic acids.
Examples of suitable acids for salt formation are hydrochloric,
sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic,
malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and
other mineral and carboxylic acids well known to those in the art.
Preferred embodiments include bisulfate salts. The salt is prepared
by contacting the free base form with a sufficient amount of the
desired acid to produce a salt. The free base form may be
regenerated by treating the salt with a suitable dilute aqueous
base solution such as dilute aqueous sodium bicatonate. The free
base form differs from its respective salt form somewhat in certain
physical properties, such as solubility in polar solvents, but the
salt is otherwise equivalent to its respective free base forms for
purposes of the invention. Compounds of the invention can also form
pharmaceutically acceptable solvates, including hydrates.
[0090] Certain compounds of the invention are acidic (e.g., those
compounds which possess a carboxyl group). These compounds form
pharmaceutically acceptable salts with inorganic and organic bases.
Examples of such salts are the sodium, potassium, calcium,
aluminum, lithium, gold and silver salts. Also included are salts
formed with pharmaceutically acceptable amines such as ammonia,
alkyl amines, hydroxyalkylamines, N-methylglucamine and the
like.
[0091] "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[0092] Compounds of the present invention in which n.sub.6 is 0 can
be prepared by processes known in the art, for example by the
processes described in U.S. Pat. No. 6,063,847, incorporated herein
by reference, and by the processes exemplified below. Compounds of
the present invention in which n.sub.6 is 1 or 2 are generally
prepared by processes in accordance with the following general
scheme: ##STR10## ##STR11## ##STR12##
[0093] Ketone 4 is subjected to a Wittig reaction to provide vinyl
ether 5 which is hydrolyzed under acidic condition to provide
aldehyde 6. The aldehyde is reduced to the alcohol 7 and converted
to azide 8 via its mesylate. Reduction of the azido group with
Me.sub.3P provides the amine 9 which is treated with different
electrophiles to provide diverse analogs.
[0094] Following are examples of preparing compounds of Formula I.
In the examples, the following abbreviations are used: Et (ethyl);
Me (methyl); Pr (propyl); Ac (acetyl); rt (room temperature), PTLC
(preparative thin layer chromatography); THF (tetrahydrofuran);
TBAF (tetra-n-butylammonium fluoride); Tips (triisopropylsilyl);
and Tf (trifluoromethanesulfonyl).
EXAMPLE 1
[0095] ##STR13## ##STR14##
[0096] Compound 1, described in U.S. Pat. No. 6,063,847, (1.95 g,
4.2 mmol) was dissolved in EtOH (40 ml) and CH.sub.2Cl.sub.2 (10
ml). Then, NH.sub.3 (g) was bubbled into the solution for 5 min.
The reaction mixture was C(O)Oled to 0.degree. C., and
Ti(O/Pr).sub.4 (1.89 ml, 6.3 mmol) was added. After stirring at
0.degree. C. for 1 h, 1M TiCl.sub.4 (6.3 ml, 6.3 mmol) was added.
The reaction mixture was stirred at rt for an additional 45 min and
concentrated to dryness under reduced pressure. The residue was
dissolved in CH.sub.3OH (10 ml) and NaBH.sub.3CN (510 mg, 8 mmol)
was added. The resulting suspension was stirred overnight at rt.
The reaction mixture was poured to 1 N NaOH (100 ml) and extracted
with EtOAc (3.times.100 ml). The organic layer was combined and
dried with Na.sub.2SO.sub.4. Removal of solvent afforded product 2
(1.2 g, 62% ). Further separation by PTLC (5% 2 M NH.sub.3 in
CH.sub.3OH/CH.sub.2Cl.sub.2) afforded .beta.-2 (spot 1) and
.alpha.-2 (spot 2) in a 1:2 ratio. .beta.-2: .sup.1HNMR
(CDCl.sub.3); .delta.0.81-1.15 (m, 2H), 1.11-1.38 (m, 4H), 1.42 (d,
J=6 Hz, 3H), 1.82-2.01 (m, 3H), 2.37 (m, 2H), 2.45 (br m, 1H), 2.65
(m, 1H), 2.81 (m, 1H), 4.75 (m, 1H), 6.61 (m, 2H), 7.26 (m, 2H),
7.75-7.85 (m, 4H), 8.77 (d, J=1.6 Hz, 1H). .alpha.-2: .sup.1HNMR
(CDCl.sub.3): .delta.0.95 (m, 1H), 1.10-1.40 (m, 5H), 1.41 (d, J=6
Hz, 3H), 1.52-1.65 (m, 2H), 1.75 (m, 1H), 1.84-2.0 (m, 2H), 2.37
(m, 1H), 2.45 (m, 1H), 2.65 (m, 1H), 3.42 (br s, 1H), 4.70 (m, 1H),
6.61 (m, 2H), 7.26 (m, 2H), 7.75-7,85 (m, 4H), 8.77 (d, J=1.6 Hz,
1H).
Step 2:
[0097] Compound .alpha.-2 (110 mg), ethyl chloroformate (0.4 ml)
and Et.sub.3N (0.5 ml) in CH.sub.2Cl.sub.2 (6 ml) were stirred for
2 h. The reaction mixture was directly separated by PTLC
(EtOAc/hexane, 1:1) to afford the title compound (100 mg, 79%). MS
m/z 543 (M+1). HRMS Calcd for C.sub.30H.sub.34N.sub.2O.sub.4F.sub.3
(M+1): 543.2471, found 543.2467.
EXAMPLE 1A
N-Methyl Compound for Comparison
[0098] ##STR15##
[0099] Compound 1 (646 mg, 1.38 mmol) was dissolved in 2.0 M
CH.sub.3NH.sub.2 in CH.sub.3OH (15 ml, 30 mmol) and stirred at rt
for 5 min followed by addition of NaCNBH.sub.3 (173 mg, 2.75 mmol).
The reaction mixture was stirred at rt overnight and concentrated
to dryness under reduced pressure. Removal of the solvent followed
by PTLC separation (7% 1 M NH.sub.3 in CH.sub.3OH/CH.sub.2Cl.sub.2)
afforded .beta.-4 (spot 1, 76 mg, 11%) and .alpha.-4 (spot 2, 100
mg, 15%). .beta.-4: .sup.1HNMR (CDCl.sub.3): .delta.1.15-1.24 (m,
5H), 1.42 (d, J=6 Hz, 3H), 1.42-1.61 (m, 2H), 1.71-1.95 (m, 4H),
2.21 (m, 1H), 2.38 (s, 3H), 2.45 (m, 1H), 2.71 (m, 1H), 2.84 (m,
1H), 4.75 (m, 1H), 6.51-6.63 (m, 2H), 7.26 (m, 2H), 7.75-7.85 (m,
4H), 8.77 (d, J=2.0 Hz, 1H). .alpha.-4: .sup.1HNMR (CDCl.sub.3):
.delta.0.95 (m, 2H), 1.10-1.40 (m, 5H), 1.41 (d, J=6 Hz, 3H),
1.82-1.95 (m, 5H), 2.38 (m, 2H), 2.42 (s, 3H), 2.65 (m, 1H), 4.79
(m, 1H), 6.51-6.63 (m, 2H), 7.26 (m, 2H), 7.75-7.85 (m, 4H), 8.77
(d, J=2.0 Hz, 1H).
[0100] Step 2:
[0101] Compound .alpha.-4 (50 mg), ethyl chloroformate (0.15 ml)
and Et.sub.3N (0.3 ml) in CH.sub.2Cl.sub.2 (5 ml) were stirred for
2 h. The reaction mixture was directly separated by PTLC
(EtOAc/hexane, 1:1) to afford the title compound (48 mg, 84%). MS
m/z 557 (M+1). HRMS Calcd for C.sub.31H.sub.36N.sub.2O.sub.4F.sub.3
(M+1): 557.2627, found 557.2620.
EXAMPLE 2
[0102] ##STR16##
[0103] Phosphonate 7, described in U.S. Pat. No. 6,063,847, (3.27
g, 8.1 mmol) was dissolved in THF (12 ml) and C(O)Oled to 0.degree.
C., followed by addition of 2.5 M n-BuLi (3.2 ml, 8.1 mmol). The
reaction mixture was stirred at 0.degree. C. for 10 min and warmed
up to rt. A solution of aldehyde 6, described in U.S. Pat. No.
6,063,847, in THF (12 ml) was added to the reaction mixture. The
reaction mixture was stirred for 30 min. Standard aqueous work-up,
followed by column chromatography (30-50% EtOAc in hexane) afforded
product 8. .sup.1HNMR (CDCl.sub.3): .delta.0.92-1.38 (m, 31H), 1.41
(d, J=6 Hz, 3H), 1.40-1.55 (m, 2H), 1.70-1.80 (m, 2H), 1.81-1.90
(m, 2H), 2.36 (m, 2H), 2.69 (m, 1H), 3.89 (m, 4H), 4.75 (m, 1H),
6.28-6.41 (m, 2H), 7.05-7.15 (m, 2H), 8.19 (br s, 1H).
##STR17##
[0104] Compound 8 (2.64 g, 4.8 mmol) was dissolved in THF (48 ml).
The reaction mixture was C(O)Oled to 0.degree. C. followed by
addition of 1 M TBAF (4.8 ml). The reaction mixture was stirred for
5 min followed by standard aqueous work-up. Column chromatography
(50% EtOAc/hexane) afforded product 9 (1.9 g, 100%). .sup.1HNMR
(CDCl.sub.3): .delta.1.15-1.55 (m, 6H), 1.41 (d, J=6 Hz, 3H),
1.70-1.82 (m, 3H), 1.85-1.90 (m, 1H), 2.36 (m, 2H), 2.69 (m, 1H),
3.91 (m, 4H), 4.75 (m, 1H), 6.18-6.45 (m, 2H), 7.19 (br s, 2H),
8.19 (br s, 1H). ##STR18##
[0105] To a solution of compound 9 (250 mg, 0.65 mmol) in pyridine
(5 ml) C(O)Oled to 0.degree. C. was added Tf.sub.2O (295 .mu.L, 2.1
mmol). The reaction mixture was stirred overnight at rt. Standard
aqueous work-up followed by column chromatography afforded product
10 (270 mg, 80%). .sup.1HNMR (CDCl.sub.3): .delta.1.15-1.55 (m,
6H), 1.41 (d, J=6 Hz, 3H), 1.70-1.82 (m, 3H), 1.85-1.90 (m, 1H),
2.36 (m, 2H), 2.69 (m, .sub.1H), 3.91 (m, 4H), 4.75 (m, 1H),
6.42-6.68 (m, 2H), 7.25 (m, 1H), 7.55 (m, 1H), 8.49 (d, J=2.8 Hz,
1H). ##STR19##
[0106] Compound 10 (560 mg, 1.1 mmol), 3-fluorophenyl boronic acid
(180 mg, 1.3 mmol) and K.sub.2CO.sub.3 (500 mg, 3.6 mmol) were
mixed with toluene (4.4 ml), H.sub.2O (1.5 ml) and EtOH (0.7 ml) in
a sealed tube. Under an atmosphere of N.sub.2, Pd(Ph.sub.3P).sub.4
(110 mg, 0.13 mmol) was added. The reaction mixture was heated at
100.degree. C. for 2 h under N.sub.2. The reaction mixture was
C(O)Oled down to rt, poured to EtOAc (30 ml) and washed with water
(2.times.20 ml). The EtOAc solution was dried with NaHCO.sub.3 and
concentrated at reduced pressure to give a residue. Preparative TLC
separation of the residue (50% EtOAc in hexane) afforded product 11
(445 mg, 89%). .sup.1HNMR (CDCl.sub.3): .delta.1.15-1.59 (m. 6H),
1.43 (d, J=6 Hz, 3H), 1.70-1.79 (m, 2H), 1.82 (m, 1H), 1.91 (m,
2H), 2.41 (m, 2H), 2.69 (m, 1H), 3.91 (m, 4H), 4.75 (m, 1H),
6.52-6.68 (m, 2H), 7.15 (m, 1H), 7.22 (m, 2H), 7.35 (m, 1H), 7.44
(m, 1H), 7.81 (m, 1H), 8.77 (d, J=1.2 Hz, .sub.1H). ##STR20##
[0107] Compound 11 (445 mg, 0.96 mmol) was dissolved in a mixture
of acetone (10 ml) and 1 N HCl (10 ml). The reaction mixture was
heated at 50.degree. C. for 1 h. Standard aqueous work-up followed
by preparative TLC separation (50% EtOAc in hexane) afforded
product 12 (356 mg, 89%). .sup.1HNMR (CDCl.sub.3): .delta.1.21-1.45
(m, 2H), 1.47 (d, J=5.6 Hz, 3H), 1.58-1.65 (m, 2H), 2.15 (m, 1H),
2.18-2.28 (m, 2H), 2.35-2.51 (m, 5H), 2.71 (m, 1H), 4.79 (m, 1H),
6.52-6.68 (m, 2H), 7.15 (m, 1H), 7.22 (m, 2H), 7.35 (m, 1H), 7.44
(m, 1H), 7.81 (m, 1H), 8.77 (d, J=1.2 Hz, 1H) ##STR21##
[0108] Compound 12 (500 mg, 4.2 mmol) was dissolved in EtOH (40 ml)
and CH.sub.2Cl.sub.2 (15 ml) NH.sub.3 (g) was bubbled into the
solution for 5 min. The reaction mixture was C(O)Oled to 0.degree.
C. followed by addition of Ti(OtPr).sub.4 (1.89 ml, 6.3 mmol).
After stirring at 0.degree. C. for 1 h 1M TiCl.sub.4 (6.3 ml, 6.3
mmol) was added. The reaction mixture was stirred at rt for 45 min
and concentrated to dryness under reduced pressure. The residue was
dissolved in CH.sub.3OH (10 ml) and NaBH.sub.3CN (510 mg, 8 mmol)
was added. The reaction mixture was stirred overnight at rt. The
reaction mixture was poured to 1 N NaOH (100 ml) and extracted with
EtOAc (3.times.100 ml). The organic layer was combined and dried
with NaHCO.sub.3. Removal of solvent and separation by PTLC (5% 2 M
NH.sub.3 in CH.sub.3OH/CH.sub.2Cl.sub.2) afforded .beta.-13 (spot
1, 30 mg, 6%) and .alpha.-13 (spot 2, 98 mg, 20%). .beta.-13:
.sup.1HNMR (CDCl.sub.3): .delta.1.50-1.38 (m, 5H), 1.42 (d, J=6 Hz,
3H), 1.51-1.75 (m, 5H), 1.84 (m, 2H), 2.38 (m, 1H), 2.45 (m, 1H),
3.38 (br s, 1H), 4.78 (m, 1H), 6.59 (m, 2H), 7.15 (m, 1H), 7.26 (m,
2H), 7.36 (m, 1H), 7.42 (m, 1H), 7.82 (m, 1H), 8.77 (d, J=2 Hz,
1H). .alpha.-13: .sup.1HNMR (CDCl.sub.3): .delta.0.95 (m, 2H),
1.02-1.35 (m, 6H), 1.41 (d, J=6 Hz, 3H), 1.82-1.95 (m, 4H), 2.37
(m, 2H), 2.69 (m, 2H), 4.71 (m, 1H), 6.71 (m, 2H), 7.11 (m, 1H),
7.25 (m, 2H), 7.38 (m, 1H), 7.42 (m, 1H), 7.80 (m, 1H), 8.76 (d,
J=1.6 Hz, 1H).
Step 7:
[0109] Compound .alpha.-13 (300 mg, 0.71 mmol) was dissolved in
CH.sub.2Cl.sub.2 (10 ml) followed by addition of Et.sub.3N (0.9
ml). The reaction mixture was C(O)Oled to 0.degree. C. and ethyl
chloroformate (0.5 ml) was added. The reaction mixture was stirred
at rt for 1 h. The reaction mixture was directly separated by
preparative TLC (EtOAc/hexane, 1:1) to give the title compound (14)
(300 mg, 86%). MS m/z 493 (M+1). HRMS Calcd for
C.sub.29H.sub.34N.sub.2O.sub.4F (M+1): 493.2503, found
493.2509.
EXAMPLE 2A
N-Methyl Compound for Comparison
[0110] ##STR22##
[0111] Compound 12 (130 mg, 0.31 mmol) was dissolved in 2.0 M
CH.sub.3NH.sub.2 in CH.sub.3OH (5 ml, 10 mmol). After stirring at
rt for 5 min, NaCNBH.sub.3 (40 mg, 0.62 mmol) was added. The
reaction mixture was stirred at rt overnight. Removal of the
solvent followed by PTLC separation (7% 1 M NH.sub.3 in
CH.sub.3OH/CH.sub.2Cl.sub.2) afforded .beta.-15 (spot 1, 20 mg,
15%) and .alpha.-15 (spot 2, 25 mg, 19%). .beta.-15: .sup.1HNMR
(CDCl.sub.3): .delta.1.15-1.25 (m, 5H), 1.42 (m, 3H), 1.42-1.61 (m,
2H), 1.75-1.90 (m, 3H), 2.25-2.45 (m, 2H), 2.41 (s, 3H), 2.70 (m,
1H), 2.85 (m, 1H), 4.75 (m, 1H),. 6.51-6.61 (m, 2H), 7.11 (m, 1H),
7.23-7.27 (m, 2H), 7.35 (m, 1H), 7.45 (m, 1H), 7.80 (m, 1H), 8.76
(d, J=2.4 Hz, 1H). .alpha.-15: .sup.1HNMR (CDCl.sub.3): .delta.0.90
(m, 2H), 1.10-1.35 (m, 5H), 1.41 (d, J=5.6 Hz, 3H), 1.82-2.01 (m,
4H), 2.36 (m. 2H), 2.39 (s, 3H), 2.55-2.65 (br s, 1H), 2.71 (m,
1H), 4.79 (m, 1H), 6.51-6.63 (m, 2H), 7.08 (m, 11H), 7.26 (m, 2H),
7.34 (m 1H), 7.42 (m, 1H), 7.81 (m, 1H), 8.76 (d, J=2.0 Hz,
1H).
Step 2:
[0112] Compound .alpha.-15 (25 mg, 0.06 mmol) was dissolved in
CH.sub.2Cl.sub.2 (5 ml) followed by addition of Et.sub.3N (0.2 ml).
The reaction mixture was C(O)Oled to 0.degree. C. and ethyl
chloroformate (0.1 m) was added. The reaction mixture was stirred
at rt for 1 h. The reaction mixture was directly separated by
preparative TLC (EtOAc/hexane, 1:1) to give the title compound (25
mg, 85%). MS m/z 507 (M+1). HRMS Calcd for
C.sub.30H.sub.36N.sub.2O.sub.4F (M+1): 507.2659, found
507.2652.
EXAMPLE 3
[0113] ##STR23##
[0114] Compound .alpha.-13 (10 mg, 0.02 mmol) was dissolved in
CH.sub.2Cl.sub.2 (3 ml) followed by addition of Et.sub.3N (0.5 ml).
The reaction mixture was C(O)Oled to 0.degree. C. and
CH.sub.3SO.sub.2Cl (0.2 ml) was added. The reaction mixture was
stirred at rt for 1 h. The reaction mixture was directly separated
by preparative TLC (EtOAc/hexane, 1:1) to give the title compound
(10 mg, 84%). MS m/z 499 (M+1). HRMS Calcd for
C.sub.27H.sub.32N.sub.2O.sub.4FS (M+1): 499.2067, found
499.2071.
EXAMPLE 4
[0115] ##STR24##
[0116] Compound .alpha.-13 (50 mg, 0.1 mmol) was dissolved in
CH.sub.2Cl.sub.2 (5 ml) followed by addition of CH.sub.3NCO (250
mg). The reaction mixture was stirred at rt for 1 h. The reaction
mixture was directly separated by preparative TLC
(CH.sub.3OH/CH.sub.2Cl.sub.2, 7%) to give the title compound (60 mg
as HCl salt, 98%). MS m/z 478 (M+1). HRMS Calcd for
C.sub.28H.sub.33N.sub.3O.sub.3F (M+1): 478.2506, found
478.2516.
EXAMPLE 5
[0117] ##STR25##
[0118] Compound .alpha.-13 (50 mg, 0.1 mmol) was dissolved in
CH.sub.2Cl.sub.2 (3 mL) followed by addition of Et.sub.3N (0.5 mL).
The reaction mixture was C(O)Oled to 0.degree. C. and acetic
anhydride (0.2 mL) was added. The reaction mixture was stirred at
rt overnight. The reaction mixture was directly separated by
preparative TLC (CH.sub.3OH/CH.sub.2Cl.sub.2, 8%) to give the title
compound (52 mg, 94%). MS m/z 463 (M+1). HRMS Calcd for
C.sub.28H.sub.32N.sub.2O.sub.3F (M+1): 463.2397, found
463.2399.
[0119] Using the methods described above, compounds of the
following structure prepared, ##STR26##
[0120] wherein R.sup.21 and R are as defined in Table 1.
TABLE-US-00001 TABLE 1 Ex. R.sup.21 R Physical data 6 --CF.sub.3
--NHCO.sub.2-t-butyl MS (M+1): observed: 571 7 --CF.sub.3
--NHCO.sub.2CH.sub.3 HRMS (M+1): observed: 529.2323 8 --CF.sub.3
--NHCO.sub.2CH.sub.2CH.sub.3 HRMS (M+1): observed: 543.2467 9
--CF.sub.3 --NHCO.sub.2CH.sub.2CH.sub.2OCH.sub.3 HRMS (M+1):
observed: 573.2569 10 H --NHCO.sub.2CH.sub.2CH.sub.3 HRMS (M+1):
observed: 475.2592 11 F ##STR27## HRMS (M+1): observed: 493.2509
12* --CF.sub.3 --N(n-Pr)CO.sub.2CH.sub.2CH.sub.3 HRMS (M+1):
observed: 585.2951 13* --CF.sub.3 --N(n-Pr)CO.sub.2CH.sub.2CH.sub.3
HRMS (M+1): observed: 585.2951 14 --CF.sub.3 ##STR28## HRMS (M+1):
observed: 513.2362 15 --CF.sub.3 ##STR29## HRMS (M+1): observed:
513.2367 16 F ##STR30## HRMS (M+1): observed: 477.2560 17 F
##STR31## HRMS (M+1): observed: 489.2557 18 F ##STR32## HRMS (M+1):
observed: 463.2401 19 --CF.sub.3 --NHCOCH.sub.2OCH.sub.3 HRMS
(M+1): observed: 543.2465 20 --CF.sub.3 --NHCOCH.sub.2OC(O)cH.sub.3
HRMS (M+1): observed: 571.2416 21 --CF.sub.3
--NHCONHCH.sub.2CH.sub.3 HRMS (M+1): observed: 542.2636 22
--CF.sub.3 --NHCONHCH.sub.3 HRMS (M+1) observed:556.2795 23 F
##STR33## HRMS (M+1): observed: 478.2511 24 F
--NHCONHCH.sub.2CH.sub.3 HRMS (M+1): observed: 492.2669 25 F
##STR34## HRMS (M+1): observed: 492.2668 26 --CF.sub.3
--NHSO.sub.2CH.sub.3 HRMS (M+1): observed: 563.2198 27 --CF.sub.3
--NHSO.sub.2CH.sub.2CH.sub.3 HRMS (M+1): observed: 549.2024 28
--CF.sub.3 --NHSO.sub.2CH.sub.2CH.sub.2CH.sub.3 HRMS (M+1):
observed: 577.2352 29 H --NHSO.sub.2CH.sub.3 HRMS (M+1): observed:
481.2164 30 --CF.sub.3 ##STR35## HRMS (M+1): observed: 549.2026 31
F ##STR36## HRMS (M+1): observed:513.2217 *Comparative example
[0121] Replacing the pyridine group of compound 1 with a quinoline
group, compounds of the following structure were prepared,
##STR37##
[0122] wherein R and Ar are as defined in Table 2: TABLE-US-00002
Table 2 Ex. Ar --R Physical data 32 ##STR38## ##STR39## MS m/z 453
(MH.sup.+) 33 ##STR40## ##STR41## MS m/z 482 (MH.sup.+) 34
##STR42## ##STR43## MS m/z 483 (MH.sup.+) 35 ##STR44## ##STR45## MS
m/z 483 (MH.sup.+) 36 ##STR46## ##STR47## MS m/z 483 (MH+) 37
##STR48## ##STR49## MS m/z 483 (MH+) 38 ##STR50## ##STR51## MS m/z
453 (MH+) 40 ##STR52## ##STR53## MS m/z 453 (MH+) 41 ##STR54##
##STR55## MS m/z 482 (MH+) 42 ##STR56## ##STR57## MS m/z 483 (MH+)
43 ##STR58## ##STR59## MS m/z 483 (MH+)
[0123] The following analogs were prepared employing further
variations of W selected from substituted phenyl and heteroaryl
groups: ##STR60##
[0124] wherein R and Ar are as defined in Table 3: TABLE-US-00003
TABLE 3 Ex. Ar --R Physical Data 44 ##STR61## ##STR62## MS m/z 476
(MH+) 45 ##STR63## ##STR64## MS m/z 493 (MH+) 46 ##STR65##
##STR66## MS m/z 521 (MH+) 47 ##STR67## ##STR68## MS m/z 506 (MH+)
48 ##STR69## ##STR70## MS m/z 477 (MH+) 49 ##STR71## ##STR72## MS
m/z 476 (MH+) 50 ##STR73## ##STR74## MS m/z 518 (MH+) 51 ##STR75##
##STR76## MS m/z 476 (MH+) 52 ##STR77## ##STR78## MS m/z 482 (MH+)
53 ##STR79## ##STR80## MS m/z 465 (MH+) 54 ##STR81## ##STR82## MS
m/z 500 (MH+) 55 ##STR83## ##STR84## MS m/z 476 (MH+) 56 ##STR85##
##STR86## MS m/z 500 (MH+) 57 ##STR87## ##STR88## MS m/z 518 (MH+)
58 ##STR89## ##STR90## MS m/z 493 (MH+) 59 ##STR91## ##STR92## MS
m/z 509 (MH+) 60 ##STR93## ##STR94## MS m/z 509 (MH+) 61 ##STR95##
##STR96## MS m/z 511 (MH+) 62 ##STR97## ##STR98## MS m/z 511 (MH+)
63 ##STR99## ##STR100## MS m/z 522 (MH+) 64 ##STR101## ##STR102##
MS m/z 522 (MH+) 65 ##STR103## ##STR104## MS m/z 505 (MH+) 66
##STR105## ##STR106## MS m/z 505 (MH+) 67 ##STR107## ##STR108## MS
m/z 537 (MH+) 68 ##STR109## ##STR110## MS m/z 523 (MH+)
EXAMPLE 69
[0125] ##STR111##
[0126] Compound 17 (100 mg, 0.239 mmol), prepared as described in
U.S. Pat. No. 6,063,847 was stirred with ammonium acetate (1.84 g,
23.9 mmol) and NaCNBH.sub.3 (24 mg, 0.38 mmol) in CH.sub.3OH (7 ml)
at rt under N.sub.2 for 16 h. The mixture was treated with
NH.sub.4OH (10 ml, 29% aqueous), diluted with CH.sub.2Cl.sub.2 (75
ml), and washed with NaHCO.sub.3 (sat.). The organic layer was
dried (MgSO.sub.4) and concentrated in vacuo. PTLC separation of
the residue with 2.0 M NH.sub.3/CH.sub.3OH--CH.sub.2Cl.sub.2 (595)
as eluent gave 18A (43 mg, 43%, lower R.sub.f), MS (ESI) m/z 421
(MH.sup.+), and 18B (17 mg, 17%, higher R.sub.f) MS (ESI) m/z 421
(MH.sup.+).
Step 2:
[0127] Compound 18A (0.100 g, 0.238 mmol) was stirred with ethyl
chloroformate (0.195 ml, 2.38 mmol) and Et.sub.3N (0.5 ml, 3.6
mmol) in CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. for 10 min and at
rt for 1 h. The mixture was diluted with EtOAc (50 ml) and washed
with NaHCO.sub.3 (sat.). The organic layer was dried (MgSO.sub.4)
and concentrated in vacuo. Flash chromatography of the residue on a
silica gel column with EtOAc-hexane (50-50) as eluent gave Example
69A (100 mg, 85%). MS (ESI) m/z 493 (MH.sup.+). Compound 32B was
similarly prepared from 18B. MS (ESI) m/z 493 (MH.sup.+).
EXAMPLE 70
[0128] ##STR112##
[0129] Using the procedure of Example 32, Step 1, starting with
compound 19 (see U.S. Pat. No. 6,063,847), prepare: 20A (lower
R.sub.f), MS (FAB) m/z 421 (MH.sup.+), and 20B (higher R.sub.f), MS
(FAB) m/z 421 (MH.sup.+).
Step 2:
[0130] Using the procedure of Example 69, Step 2, Example 70A was
prepared from compound 2A: MS (ESI) m/z 493 (MH.sup.+). Using the
procedure of Example 69, Step 2, Example 70B was prepared from
compound 20B: MS (ESI) m/z 493 (MH.sup.+).
EXAMPLE 71
[0131] ##STR113##
[0132] Lactone 21, described in U.S. Pat. No. 6,063,847 (10 g,
0.0251 mol) was dissolved in acetone, 1 N HCl was added and the
mixture heated at 55.degree. C. for 4 h. The mixture was allowed to
C(O)Ol to rt, neutralized with NaHCO.sub.3, and extracted with
EtOAc. The extracts were dried and concentrated under reduced
pressure to give 22 (7.35 g) as oil. MS m/z 355 (M+1).
##STR114##
[0133] Ketone 22 (7.35 g, 0.0207 mol) was dissolved in THF and
C(O)Oled to 0.degree. C. Potassium tert-butoxide was added (2.55 g,
1.1 eq). After stirring for 10 min, CH.sub.3l (2.58 ml, 2 eq) was
added. The mixture was stirred for 2.5 h. Aqueous work-up with
NH.sub.4Cl.sub.(sat) followed by column chromatography (30-50%
EtOAc in hexane) gave 23 (1.63 g). MS m/z 383 (M+1). ##STR115##
[0134] Ketone 23 (1.634 g, 0.00426 mol) was dissolved in
CH.sub.3OH, NH.sub.4OAc and NaCNBH.sub.3 were added. The mixture
was stirred for 2 h. The reaction was quenched with NH.sub.4OH and
the mixture extracted with CH.sub.2Cl.sub.2. The organic extracts
were dried and concentrated to give an oil. MS m/z 383 (M+1).
[0135] The oil was dissolved in CH.sub.2Cl.sub.2, Et.sub.3N was
added and the mixture C(O)Oled to 0.degree. C. Ethyl chloroformate
was added and the mixture was stirred overnight. Aqueous work-up
with NH.sub.4Cl.sub.(sat) followed by column chromatography (30%
EtOAc in hexane) gave 0.797 g of an inseparable 3:1 mixture of
.alpha.-24 and .beta.-24, MS m/z 456 (M+1). ##STR116##
[0136] The product mixture from step 3 (330 mg, 0.724 mmol) was
dissolved in EtOAc (14 ml) and Pd(C) (10% by wt) was added. The
mixture was stirred under H.sub.2 (1 atm) for 2 h. The mixture was
filtered, concentrated, and dissolved in CH.sub.3OH (15 ml).
PtO.sub.2 (10% by wt) was added, the mixture was placed under
H.sub.2 atmosphere (50 psi), and agitated on a parr shaker for 3
days. The mixture was filtered and concentrated to give 280 mg of
acids 25. MS m/z 368 (M+1). ##STR117##
[0137] The crude acids 25 (0.724 mmol) were dissolved in
CH.sub.2Cl.sub.2, (COCl).sub.2 (0.1 ml, 1.5 eq) and a drop of DMF
were added. The mixture was stirred for 30 min, when .sup.1H NMR
showed complete conversion. The CH.sub.2Cl.sub.2 was replaced with
toluene and the resulting solution was C(O)Oled to 0.degree. C.
Pd(Ph.sub.3P).sub.4 was added, followed by dropwise addition of
Bu.sub.3SnH. After stirring at 0.degree. C. for 30 min, TLC showed
complete reaction. Column chromatography (20-50% EtOAc in hexane)
gave 248 mg of aldehydes 26. MS m/z 352 (M+1). ##STR118##
[0138] Phosphonate 27 (248 mg, 0.768 mmol, 3 eq), see U.S. Pat. No.
6,063,847, was dissolved in THF (4 ml) and the mixture was C(O)Oled
to 0.degree. C. LHMDS (0.768 ml, 3 eq of a 1M solution in THF) was
added and the resulting mixture stirred for 30 min. Ti(i-OPr).sub.4
(0.227 ml, 3 eq.) was added and 5 min later a solution of aldehydes
26 (90 mg, 0.256 mol) in THF (4 ml) was added. The mixture was
stirred for 1.5 h when TLC showed complete conversion. Saturated
sodium potassium tartrate was added and the THF removed under
vacuum. The residue was extracted with EtOAc, dried, concentrated
and purified by PTLC (1:1 EtOAc/hexane) to give the title compound
(80 mg). MS m/z 521 (M+1).
EXAMPLE 72
[0139] ##STR119##
[0140] To solution of 1.35 g (2.75 mmol) of starting material, 0.57
ml of Et.sub.3N (4.13 mmol, 1.5 equiv.) and 70 mg of DMAP (0.57
mmol, 0.2 equiv.) in 20 ml CH.sub.3CN at 60.degree. C. was added 2
equivalents of (Boc).sub.2O. Subsequently, 5 equivalents of
(Boc).sub.2O was introduced over a period of 5 hr. The solution was
C(O)Oled, concentrated and chromatographed to provide 0.86 g of
product. [0141] MS: 593.1 (MH.sup.+) ##STR120##
[0142] To a solution of 280 mg (0.47 mmol) of starting material in
5 ml THF at 0.degree. C. was added 0.95 ml (0.95 mmol, 2 equiv.) of
1M LHMDS in THF. The mixture was stirred for 30 min. and O.sub.2
was introduced via a balloon. After stirring for 1 hr, the reaction
was quenched with the addition of 50 ml of aq. Na.sub.2SO.sub.3 and
stirred for 1 hr. The aqueous layer was extracted with 3.times.25
ml of ethylacetate and the combined organic layer was washed with
brine, dried over MgSO.sub.4 and chromatographed with 30%
EtOAc-hexanes to afford 125 mg of hydroxylated product.
##STR121##
[0143] To a solution of 125 mg of starting material in 1 ml
CH.sub.2Cl.sub.2 at room temperature was added 1 ml of
trifluoroacetic acid, stirred for 1 hr and concentrated. To this
was added 50 ml of aq. Na.sub.2CO.sub.3 and extracted with
3.times.10 ml CH.sub.2Cl.sub.2. The combined organic layer was
washed with 10 ml brine, dried over MgSO.sub.4, filtered,
concentrated and chromatographed with 50% EtOAc-hexanes to provide
90 mg of product. [0144] HRMS: 509.2459 (MH.sup.+)
EXAMPLE 73
[0145] ##STR122##
[0146] To a solution of 500 mg (0.84 mmol) of starting material in
8 ml THF was added 1.7 ml (1.7 mmol, 2 equiv.) of 1M LHMDS in THF.
The solution was stirred for 30 min. and C(O)Oled to -78.degree.
C., and a solution of 390 mg (1.7 mmol, 2 equiv.) di-tert-butyl
azodicarboxylate (DBAD) in 2 ml THF was added. The reaction was
allowed to warm to room temperature over a period of 3 hr, poured
into 100 ml aq. NH.sub.4Cl and extracted with 3.times.30 ml of
EtOAc. The combined organic layers were washed with 30 ml brine,
dried over MgSO.sub.4, filtered and concentrated to provide the
crude product.
[0147] This was stirred with 15 ml of 1:1 TFA-DCM at room
temperature for 1 hr, concentrated and basified with 100 ml of aq.
Na.sub.2CO.sub.3. The aqueous layer was extracted with 3.times.25
ml of DCM, combined organic layers were washed with 25 ml brine,
dried over MgSO.sub.4, filtered and concentrated to provide the
crude hydrazide.
[0148] The crude hydrazide was dissolved in 10 ml of glacial acetic
acid and 2 g of Zn powder was added in small portions and stirred
for about 1.5 hr. It was filtered through celite and rinsed with
100 ml of DCM. The DCM solution was washed with 2.times.50 ml
H.sub.2O, 2.times.50 ml aq. NaHCO.sub.3, 50 ml brine, dried over
MgSO.sub.4, filtered, concentrated and chromatographed with 87:10:3
DCM-acetone-MeOH to provide 105 mg of product. [0149] HRMS:
508.2607 (MH.sup.+)
EXAMPLE 74
[0150] ##STR123##
[0151] To a suspension of (methoxymethyl)triphenylphosphonium
chloride (3.20 g, 9.34 mmol) in 30 ml THF at 0.degree. C. was added
1M .sup.1BuOK in THF (10.3 ml, 10.3 mmol) and stirred for 30 min.
To this solution was added a solution of ketone (1.95 g, 4.65 mmol)
in 25 ml THF and 10 ml DMF. The mixture was stirred at room
temperature for 1 hr, poured into 300 ml aq. NH.sub.4Cl and
extracted with 3.times.75 ml EtOAc. The combined organic layers
were washed with 75 ml brine, dried over MgSO.sub.4, filtered,
concentrated and chromatographed with 40% EtOAc-hexanes to provide
1.679 of product. [0152] MS: 448.1 (MH.sup.+) ##STR124##
[0153] A solution of 1.67 g of vinyl ether in 15 ml of 4N HCl in
dioxane and 1.5 ml H.sub.2O was stirred at room temperature for 1.5
hr, poured into 250 ml of aq. Na.sub.2CO.sub.3 and extracted with
3.times.50 ml of DCM. The combined organic layers were washed with
50 ml brine, dried over MgSO.sub.4, filtered, concentrated and
chromatographed with 40% EtOAc-hexanes to provide 1.36 g of
aldehyde.
[0154] To a solution of this aldehyde in 20 ml MeOH and 10 ml THF
at 0.degree. C. was added 120 mg of NaBH.sub.4 and stirred for 10
min. It was poured into 150 ml of aq. NH.sub.4Cl, and extracted
with 3.times.50 ml EtOAc. The combined organic layer was washed
with 50 ml brine, dried over MgSO.sub.4, filtered and concentrated
to provide 1.27 g alcohol as white solid. [0155] HRMS: 436.2275
(MH.sup.+) ##STR125##
[0156] To a solution of alcohol (1.27 g, 2.92 mmol) in 20 ml DCM at
ca. -40.degree. C. was added 0.63 ml of Et.sub.3N and 0.27 ml of
MeSO.sub.2Cl and the solution was allowed to warm up to 0.degree.
C. over a period of 1 hr. Then another 0.16 ml of Et.sub.3N and
0.07 ml of MeSO.sub.2Cl was added and stirred for another 1 hr at
0.degree. C. It was diluted with 100 ml EtOAc and washed with
2.times.30 ml aq. NaHCO.sub.3, 30 ml brine, dried over MgSO.sub.4,
filtered and concentrated to provide 1.6 g of mesylate.
[0157] A solution of the above mesylate was stirred with 950 mg of
NaN.sub.3 (14.6 mmol, 5 equiv.) in 10 ml DMSO at 65.degree. C. for
1.5 hr. It was diluted with 150 ml of EtOAc, washed with 3.times.50
ml H.sub.2O, 50 ml brine, dried over MgSO.sub.4, filtered and
concentrated to provide 1.3 g of azide.
[0158] To a solution of this azide in 15 ml EtOAc and 0.2 ml
H.sub.2O at 0.degree. C. was added 1M Me.sub.3P in THF and stirred
at room temperature for 4 hr. It was concentrated and
chromatographed with 4% MeOH-DCM to provide 1.06 g of amine. [0159]
HRMS: 435.2445 (MH.sup.+)
EXAMPLES 75-84
[0160] ##STR126##
[0161] Using the methods described above, the amine was treated
with different electrophiles and compounds of the following
structure were prepared, ##STR127##
[0162] wherein R is as defined in Table 4: TABLE-US-00004 TABLE 4
Ex. R HRMS (MH.sup.+) 74 H 435.2445 75 ##STR128## 507.2664 76
##STR129## 493.2497 77 ##STR130## 477.2548 78 ##STR131## 491.2703
79 ##STR132## 513.2213 80 ##STR133## 527.2388 81 ##STR134##
506.2822 82 ##STR135## 532.2970 83 ##STR136## 506.2822 84
##STR137## 546.3124
EXAMPLES 85-92
[0163] ##STR138##
[0164] To a solution of aldehyde (2.19 g, 4.53 mmol) in 40 ml
CH.sub.3CN and 5 ml DCM was added a solution of NaH.sub.2PO.sub.4
(135 mg, 1.13 mmol, 0.25 equiv.) and 30% aq. H.sub.2O.sub.2 (0.51
ml 4.99 mmol, 1.1 equiv.) in 8 ml H.sub.2O. To this was added a
solution of80% NaClO.sub.2 (0.72 g, 6.37 mmol, 1.4 equiv.) in 5 ml
H.sub.2O and the mixture was stirred at room temperature for 2 hr.
It was diluted with 150 ml H.sub.2O, acidified with 1N HCl to ca.
pH 3 and extracted with 3.times.50 ml DCM. The combined organic
layers were washed with 50 ml brine, dried over MgSO.sub.4,
filtered, concentrated to provide 2.2 g of carboxylic acid as
solid. [0165] HRMS: 450.2077 (MH.sup.+) ##STR139##
[0166] General Procedure:
[0167] To a solution of acid and amine (3 equiv.) in DMF-DCM
mixture was added HATU (2 equiv.) and stirred overnight at room
temperature. It was diluted with EtOAc, washed with aq.
NaHCO.sub.3, brine, dried over MgSO.sub.4, filtered, concentrated
and chromatographed to provide the amide.
[0168] Using the methods described above, compounds of the
following structure were prepared: ##STR140##
[0169] wherein NRR' is as defined in Table 5: TABLE-US-00005 TABLE
5 EX. NRR' (MH+) HRMS 85 ##STR141## 576.2481 86 ##STR142## 576.2472
87 ##STR143## 513.2370 88 ##STR144## 527.2517 89 ##STR145##
543.2477 90 ##STR146## 541.2669 91 ##STR147## 569.2632 92
##STR148## 569.2627
[0170] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), The Science and Practice of Pharmacy, 20.sup.th
Edition, Lippincott Williams & Wilkins, Baltimore, Md.,
(2000).
[0171] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection and addition of
sweeteners and opacifiers for oral solutions, suspensions and
emulsions. Liquid form preparations may also include solutions for
intranasal administration.
[0172] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g., nitrogen.
[0173] Also included are solid form preparations which are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0174] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0175] Preferably the compound is administered orally.
[0176] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0177] The daily dose of a compound of Formula I for treatment of a
disease or condition cited above is about 0.001 to about 100 mg/kg
of body weight per day, preferably about 0.001 to about 10 mg/kg.
For an average body weight of 70 kg, the dosage level is therefore
from about 0.1 to about 700 mg of drug per day, given in a single
dose or 2-4 divided doses.
[0178] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated.
[0179] Further embodiments of the invention encompass the
administration of compounds of Formula I along with at least one
additional cardiovascular agent. The contemplated additional
cardiovascular agent is one that differs in either atomic make up
or arrangement from the compounds of Formula I. Additional
cardiovascular agents that can be used in combination with the
novel compounds of this invention include drugs which have
anti-thrombotic, anti-platelet aggregation, antiatherosclerotic,
antirestenotic and/or anti-coagulant activity. Such drugs are
useful in treating thrombosis-related diseases including
thrombosis, atherosclerosis, restenosis, hypertension, angina
pectoris, arrhythmia, heart failure, myocardial infarction,
glomerulonephritis, thrombotic and thromboembolic stroke,
peripheral vascular diseases, other cardiovascular diseases,
cerebral ischemia, inflammatory disorders and cancer, as well as
other disorders in which thrombin and its receptor play a
pathological role. Suitable cardiovascular agents are selected from
the group consisting of thromboxane A2 biosynthesis inhibitors such
as aspirin; thromboxane antagonists such as seratrodast, picotamide
and ramatroban; adenosine diphosphate (ADP) inhibitors such as
clopidogrel; cyclooxygenase inhibitors such as aspirin, meloxicam,
rofecoxib and celecoxib; angiotensin antagonists such as valsartan,
telmisartan, candesartran, irbesartran, losartan and eprosartan;
endothelin antagonists such as tezosentan; phosphodiesterase
inhibitors such as milrinoone and enoximone; angiotensin converting
enzyme (ACE) inhibitors such as captopril, enalapril, enaliprilat,
spirapril, quinapril, perindopril, ramipril, fosinopril,
trandolapril, lisinopril, moexipril and benazapril; neutral
endopeptidase inhibitors such as candoxatril and ecadotril;
anticoagulants such as ximelagatran, fondaparin and enoxaparin;
diuretics such as chlorothiazide, hydrochlorothiazide, ethacrynic
acid, furosemide and amiloride; platelet aggregation inhibitors
such as abciximab and eptifibatide; and GP IIb/IIIa
antagonists.
[0180] Preferred types of drugs for use in combination with the
novel compounds of this invention are thromboxane A2 biosynthesis
inhibitors, cyclooxygenase inhibitors and ADP antagonists.
Especially preferred for use in the combinations are aspirin and
clopidogrel bisulfate.
[0181] When the invention comprises a combination of a compound of
Formula I and another cardiovascular agent, the two active
components may be co-administered simultaneously or sequentially,
or a single pharmaceutical composition comprising a compound of
Formula I and another cardiovascular agent in a pharmaceutically
acceptable carrier can be administered. The components of the
combination can be administered individually or together in any
conventional dosage form such as capsule, tablet, powder, cachet,
suspension, solution, suppository, nasal spray, etc. The dosage of
the cardiovascular agent can be determined from published material,
and may range from 1 to 1000 mg per dose.
[0182] In this specification, the term "at least one compound of
Formula I" means that one to three different compounds of Formula I
may be used in a pharmaceutical composition or method of treatment.
Preferably one compound of Formula I is used. Similarly, the term
"one or more additional cardiovascular agents" means that one to
three additional drugs may be administered in combination with a
compound of Formula I; preferably, one additional compound is
administered in combination with a compound of Formula I. The
additional cardiovascular agents can be administered sequentially
or simultaneously with reference to the compound of Formula I.
[0183] When separate compounds of Formula I and the other
cardiovascular agents are to be administered as separate
compositions, they can be provided in a kit comprising in a single
package, one container comprising a compound of Formula I in a
pharmaceutically acceptable carrier, and a separate container
comprising another cardiovascular agent in a pharmaceutically
acceptable carrier, with the compound of Formula I and the other
cardiovascular agent being present in amounts such that the
combination is therapeutically effective. A kit is advantageous for
administering a combination when, for example, the components must
be administered at different time intervals or when they are in
different dosage forms.
[0184] The activity of the compounds of Formula I can be determined
by the following procedures.
In Vitro Testing Procedure for Thrombin Receptor Antagonists:
[0185] Preparation of [.sup.3H]haTRAP
[0186] A(pF-F)R(ChA)(hR)(I.sub.2-Y)-NH.sub.2 (1.03 mg) and 10% Pd/C
(5.07 mg) were suspended in DMF (250 .mu.l) and
diisopropylethylamine (10 .mu.l). The vessel was attached to the
tritium line, frozen in liquid nitrogen and evacuated. Tritium gas
(342 mCi) was then added to the flask, which was stirred at room
temperature for 2 hours. At the completion of the reaction, the
excess tritium was removed and the reacted peptide solution was
diluted with DMF (0.5 ml) and filtered to remove the catalyst. The
collected DMF solution of the crude peptide was diluted with water
and freeze dried to remove the labile tritium. The solid peptide
was redissolved in water and the freeze drying process repeated.
The tritiated peptide ([.sup.3H]haTRAP) was dissolved in 0.5 ml of
0.1% aqueous TFA and purified by HPLC using the following
conditions: column, Vydac C18, 25 cm.times.9.4 mm I.D.; mobile
phase, (A) 0.1% TFA in water, (B) 0.1% TFA in CH.sub.3CN; gradient,
(A/B) from 100/0 to 40/60 over 30 min; flow rate, 5 ml /min;
detection, UV at 215 nm. The radiochemical purity of
[.sup.3H]haTRAP was 99% as analyzed by HPLC. A batch of 14.9 mCi at
a specific activity of 18.4 Ci/mmol was obtained.
[0187] Preparation of Platelet Membranes
[0188] Platelet membranes were prepared using a modification of the
method of Natarajan et al (Natarajan et al, Int. J. Petide Protein
Res., vol. 45, pp. 145-151 (1995) from 20 units of platelet
concentrates obtained from the North Jersey Blood Center (East
Orange, N.J.) within 48 hours of collection. All steps were carried
out at 40.degree. C. under approved biohazard safety conditions.
Platelets were centrifuged at 100.times.g for 20 minutes at
40.degree. C. to remove red cells. The supernatants were decanted
and centrifuged at 3000.times.g for 15 minutes to pellet platelets.
Platelets were resuspended in 10 mM Tris-HCl, pH 7.5, 150 mM NaCl,
5 mM EDTA, to a total volume of 200 ml and centrifuged at
4400.times.g for 10 minutes. This step was repeated two additional
times. Platelets were resuspended in 5 mM Tris-HCl, pH 7.5, 5 mM
EDTA to a final volume of approximately 30 ml and were homogenized
with 20 strokes in a Dounce homogenizer. Membranes were pelleted at
41,000.times.g, resuspended in 40-50 ml 20 mM Tris-HCl, pH 7.5, 1
mM EDTA, 0.1 mM dithiothreitol, and 10 ml aliquots were frozen in
liquid N.sub.2 and stored at -80.degree. C. To complete membrane
preparation, aliquots were thawed, pooled, and homogenized with 5
strokes of a Dounce homogenizer. Membranes were pelleted and washed
3 times in 10 mM triethanolamine-HCl, pH 7.4, 5 mM EDTA, and
resuspended in 20-25 ml 50 mM Tris-HCl, pH 7.5, 10 mM MgCl.sub.2, 1
mM EGTA, and 1% DMSO. Aliquots of membranes were frozen in liquid
N.sub.2 and stored at -80.degree. C. Membranes were stable for at
least 3 months. 20 units of platelet concentrates typically yielded
250 mg of membrane protein. Protein concentration was determined by
a Lowry assay (Lowry et al, J. Biol. Chem., vol. 193, pp. 265-275
(1951).
High Throughput Thrombin Receptor Radioligand Binding Assay
[0189] Thrombin receptor antagonists were screened using a
modification of the thrombin receptor radioligand binding assay of
Ahn et al. (Ahn et al, Mol Pharmacol., vol. 51, p. 350-356 (1997).
The assay was performed in 96 well Nunc plates (Cat. No. 269620) at
a final assay volume of 200 .mu.l. Platelet membranes and
[.sup.3H]haTRAP were diluted to 0.4 mg/ml and 22.2 nM,
respectively, in binding buffer (50 mM Tris-HCl, pH 7.5, 10 mM
MgCl.sub.2, 1 mM EGTA, 0.1% BSA). Stock solutions (10 mM in 100%
DMSO) of test compounds were further diluted in 100% DMSO. Unless
otherwise indicated, 10 .mu.l of diluted compound solutions and 90
.mu.l of radioligand (a final concentration of 10 nM in 5% DMSO)
were added to each well, and the reaction was started by the
addition of 100 .mu.l of membranes (40 .mu.g protein/well). The
binding was not significantly inhibited by 5% DMSO. Compounds were
tested at three concentrations (0.1, 1 and 10 .mu.M). The plates
were covered and vortex-mixed gently on a Lab-Line Titer Plate
Shaker for 1 hour at room temperature. Packard UniFilter GF/C
filter plates were soaked for at least 1 hour in 0.1%
polyethyleneimine. The incubated membranes were harvested using a
Packard FilterMate Universal Harvester and were rapidly washed four
times with 300 .mu.l ice cold 50 mM Tris-HCl, pH 7.5, 10 mM
MgCl.sub.2, 1 mM EGTA. MicroScint 20 scintillation cocktail (25
.mu.l) was added to each well, and the plates were counted in a
Packard TopCount Microplate Scintillation Counter. The specific
binding was defined as the total binding minus the nonspecific
binding observed in the presence of excess (50 .mu.M) unlabeled
haTRAP. The % Inhibition by a compound of [.sup.3H]haTRAP binding
to thrombin receptors was calculated from the following
relationship: % Inhibition= Total .times. .times. binding - Binding
.times. .times. in .times. .times. the .times. .times. presence
.times. .times. of .times. .times. a .times. .times. test .times.
.times. compound Total .times. .times. binding - Nonspecific
.times. .times. binding 100 ##EQU1##
[0190] Affinity values (K.sub.i) were then determined using the
following formula: K i = IC 50 1 + [ concentration .times. .times.
of .times. .times. radioligand affinity .times. .times. ( K D )
.times. .times. of .times. .times. radioligand ] ##EQU2## Hence, a
lower value of K.sub.i indicates greater binding affinity.
Materials
[0191] A(pF-F)R(ChA)(hR)Y-NH.sub.2 and A(pF-F)R(ChA)(hR)(I.sub.hd
2-Y)-NH.sub.2, were custom synthesized by AnaSpec Inc. (San Jose,
Calif.). The purity of these peptides was >95%. Tritium gas
(97%) was purchased from EG&G Mound, Miamisburg Ohio. The gas
was subsequently loaded and stored on an IN/US Systems Inc.
Trisorber. MicroScint 20 scintillation cocktail was obtained from
Packard Instrument Co.
Protocol for Ex-Vivo Platelet Aggregation in Cynomolgus Whole Blood
Drug Administration and Blood Collection.
[0192] Conscious chaired cynomolgus monkeys are allowed to
equilibrate for 30 min. A needle catheter is inserted into a
brachial vein for infusion of test drugs. Another needle catheter
is inserted into the other brachial or saphenous vein and used for
blood sampling. In those experiments where the compound is
administered orally only one catheter is used. A baseline blood
sample (1-2 ml) is collected in vacutainer tubes containing a
thrombin inhibitor CVS 2139 (100 .mu.g/0.1 ml saline) as an
anticoagulant. The drug is then infused intravenously over a period
of 30 min. Blood samples (1 ml) are collected at 5, 10, 20, 30 min
during and 30, 60, 90 min after termination of the drug infusion.
In PO experiments the animals are dosed with the drug using a
gavage cannula. Blood samples are collected at 0, 30, 60, 90, 120,
180, 240, 300, 360 min after dosing. 0.5 ml of the blood is used
for whole blood aggregation and the other 0.5 ml is used for
determining the plasma concentration of the drug or its
metabolites. Aggregation is performed immediately after collection
of the blood sample as described below.
Whole Blood Aggregation
[0193] A 0.5 ml blood sample is added to 0.5 ml of saline and
warmed to 37.degree. C. in a Chronolog whole blood aggregometer.
Simultaneously, the impedance electrode is warmed in saline to
37.degree. C. The blood sample with a stir bar is placed in the
heating block well, the impedance electrode is placed in the blood
sample and the collection software is started. The software is
allowed to run until the baseline is stabilized and then a 20
.OMEGA. calibration check is performed. 20 .OMEGA. is equal to 4
blocks on the graphic produced by the computer software. The
agonist (haTRAP) is added by an adjustable volume pipette (5-25
.mu.l) and the aggregation curve is recorded for 10 minutes.
Maximum aggregation in 6 minutes following agonist addition is the
value recorded.
In Vitro Platelet Aggregation Procedure:
[0194] Platelet aggregation studies were performed according to the
method of Bednar et al. (Bednar, B., Condra, C., Gould, R. J., and
Connolly, T. M., Throm. Res., vol. 77, pp. 453-463 (1995)). Blood
was obtained from healthy human subjects who were aspirin free for
at least 7 days by venipuncture using ACD as anticoagulant.
Platelet rich plasma was prepared by centrifugation at 100.times.g
for 15 minutes at 15 deg C. Platelets were pelleted at 3000.times.g
and washed twice in buffered saline containing 1 mM EGTA and 20
.mu.g/ml apyrase to inhibit aggregation. Aggregation was performed
at room temperature in buffered saline supplemented with 0.2 mg/ml
human fibrinogen. Test compound and platelets were preincubated in
96-well flat-bottom plates for 60 minutes. Aggregation was
initiated by adding 0.3 .mu.M haTRAP or 0.1 U/ml thrombin and
rapidly vortexing the mixture using a Lab Line Titer Plate Shaker
(speed 7). Percent aggregation was monitored as increasing light
transmittance at 405 nm in a Spectromax Plate Reader.
In Vivo Antitumor Procedure:
[0195] Tests in the human breast carcinoma model in nude mouse are
conducted according to the procedure reported in S. Even-Ram et.
al., Nature Medicine, 4, 8, pp. 909-914 (1988).
[0196] Compounds of the present invention are surprisingly active
in the ex-vivo platelet aggregation test model. In these studies,
the compound of Example 2 of this invention, after oral
administration at a dose of 0.1 mg/kg, completely inhibited
aggregation of platelets induced by exogenously added thrombin
receptor activating peptide for duration of 24 hours. Even after 48
hours, approximately 65% of inhibition of platelet aggregation was
sustained. In contrast, N-alkyl carbamate analogs, Examples 1A, 2A
and 13 of U.S. Pat. No. 6,063,847, were studied under similar
conditions using a dose of 0.5 mg/kg, a 5-fold increase over the
dose of the compound of Example 2. Under these conditions, the
N-alkyl compounds showed no significant inhibition of platelet
aggregation at various time points.
[0197] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and variations thereof will be apparent
to those of ordinary skill in the art. All such alternatives,
modifications, and variations are intended to fall within the
spirit and scope of the present invention.
* * * * *