Thrombin or factor Xa inhibitors

Details Thrombin or factor Xa inhibitors Thrombin or factor Xa inhibitors

2001-12-04

2003-08-05

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S350000, C544S237000, C544S284000, C514S252010, C514S252030, C514S252130, C514S252140, C514S266200, C514S211100, C540S503000

Reexamination Certificate

active

06602871

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca
2+
and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation.
Thromb. Res.
1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa, thrombin, or both are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa, thrombin, or both inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrug thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of thrombosis or a disease mediated by factor Xa.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides a novel compound selected from the group:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
G is selected from the group:
L
n
is a linker which is absent or is selected from O, S, CH
2
, *CH
2
NHC(O), *CH(R
a
)NHC(O), *CH
2
NHC(O)CH
2
, and *CH(R
a
)NHC(O)CH
2
, provided that L
n
and M do not form an O—N or S—N bond and the * indicates where L
n
is bonded to G;
M
1
is absent or is CHR;
M
2
is N or CR
f
;
M
3
is N or CR
d
;
provided that only one of M
2
and M
3
is N;
R
a
is selected from C(O)C(O)OR
3
, C(O)C(O)NR
2
R
2a
, and C(O)-A;
R
b
is selected from H, R, phenyl, C
1-10
alkyl, and C
2-5
alkenyl;
R
c
is selected from H and C
1-6
alkyl;
alternatively, R
b
and R
c
together are —(CH
2
)
4
—;
R
d
is selected from H, F, and Cl;
R
e
is selected from H, N(CH
3
) (CH
2
CO
2
H) and S-(5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4
);
alternatively, R
d
and R
e
combine to form —NR
3
—C(O)—C(R
1b
R
3
)—NR
3
— or —N═CR
2
—NR
3
—;
R
f
is selected from H, F, and Cl;
alternatively, R
e
and R
f
combine to form —NR
3
—C(R
1b
R
3
)—C(O)—NR
3
— or —NR
3
—CR
2
═N—;
R
g
is selected from H, CH
2
OR
3
, CH
2
C(O)OR
3
, C
1-4
alkyl, C(O)NH
2
, and NH
2
;
R
h
is selected from H, CH
2
-phenyl, CH
2
CH
2
-phenyl, and CH═CH-phenyl;
R
i
is selected from SO
2
CH
2
C(O)OR
3
, C(O)CH
2
C(O)OR
3
, and C(O)OR
3
;
R is selected from H, Cl, F, Br, I, (CH
2
)
t
OR
3
, C
1-4
alkyl, benzyl, OCF
3
, CF
3
, C(O)NR
7
R
8
, and (CR
8
R
9
)
t
NR
7
R
8
;
Z is selected from (CR
8
R
9
)
1-4
, (CR
8
R
9
)
r
O (CR
8
R
9
)
r
, (CR
8
R
9
)
r
NR
3
(CR
8
R
9
)
r
, (CR
8
R
9
)
r
C(O) (CR
8
R
9
)
r
, (CR
8
R
9
)
r
C(O)O(CR
8
R
9
)
r
, (CR
8
R
9
)
r
OC(O)(CR
8
R
9
)
r
, (CR
8
R
9
)
r
C(O)NR
3
(CR
8
R
9
)
r
, (CR
8
R
9
)
r
NR
3
C(O)(CR
8
R
9
)
r
, (CR
8
R
9
)
r
OC(O)O(CR
8
R
9
)
r
, (CH
2
)
r
OC(O)NR
3
(CR
8
R
9
)
r
, (CR
8
R
9
)
r
NR
3
C(O)O(CR
8
R
9
)
r
, (CH
2
)
r
NR
3
C(O)NR
3
(CR
8
R
9
)
r
, (CR
8
R
9
)
r
S(O)
p
(CR
8
R
9
)
r
, (CR
8
R
9
)
r
S(O)
2
(CH═CH), (CCR
8
R
9
)
r
SO
2
NR
3
(CR
8
R
9
)
r
, (CR
8
R
9
)
r
NR
3
SO
2
(CR
8
R
9
)
r
, and (CR
8
R
9
)
r
NR
3
SO
2
NR
3
(CR
8
R
9
)
r
, provided that Z does not form a N—N, N—O, N—S, NCH
2
N, NCH
2
O, or NCH
2
S bond with the groups to which Z is attached;
R
1a
is absent or selected from —(CH
2
)
r
—R
1′
, —CH═CH—R
1′
, NHCH
2
R
1″
, OCH
2
R
1″
, SCH
2
R
1″
, NH(CH
2
)
2
(CH
2
)
t
R
1′
, O(CH
2
)
2
(CH
2
)
t
R
1′
, and S(CH
2
)
2
(CH
2
)
t
R
1′
;
R
1′
is selected from H, C
1-3
alkyl, F, Cl, Er, I, —CN, —CHO, (CF
2
)
r
CF
3
, (CH
2
)
r
OR
2
, NR
2
R
2a
, C(O)R
2c
, OC(O)R
2
, (CF
2
)
r
CO
2
R
2c
, S(O)
p
(CH
2
)
r
R
2b
, NR
2
(CH
2
)
r
OR
2
, C(═NR
2c
)NR
2
R
2a
, NR
2
C(O)R
2b
, NR
2
C(O)NHR
2b
, NR
2
C(O)
2
R
2a
, OC(O)NR
2a
R
2b
, C(O)NR
2
R
2a
, C(O)NR
2
(CH
2
)
r
OR
2
, SO
2
NR
2
R
2a
, NR
2
SO
2
R
2b
, C
3-6
carbocyclic residue substituted with 0-2 R
4
, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4
;
R
1″
is selected from H, CH(CH
2
OR
2
)
2
, C(O)R
2c
, C(O)NR
2
R
2a
, S(O)R
2b
, S(O)
2
R
2b
, and SO
2
NR
2
R
2a
;
R
1b
is selected from H, C
1-6
alkyl, and C
1-6
alkyl substituted with A;
R
2
, at each occurrence, is selected from H, CF
3
, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
R
2a
, at each occurrence, is selected from H, CF
3
, C
1-6
alkyl, benzyl, C
3-6
cycloalkylmethyl substituted with 0-2 R
4b
, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
R
2b
, at each occurrence, is selected from CF
3
, C
1-4
alkoxy, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
R
2c
, at each occurrence, is selected from CF
3
, OH, C
1-4
alkoxy, C
1-6
alkyl, benzyl, C
3-6
carbocyclic residue substituted with 0-2 R
4b
, and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R
4b
;
alternatively, R
2
and R
2a
, together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R
4b
and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
R
3
, at each occurrence, is selected from H, C
1-4
alkyl, and phenyl;
R
3a
, at each occurrence, is selected from H, C
1-4
alkyl, and phenyl;
R
3b
, at each occurrence, is selected from H, C
1-4
alkyl, and phenyl;
R
3c
, at each occurrence, is selected from C
1-4
alkyl, and phenyl;
A is selected from:
C
3-10
carbocyclic residue substituted with 0-2 R
4
, and
5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the grou

Affiliated with

Also associated with

Rating

Thrombin or factor Xa inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Thrombin or factor Xa inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Thrombin or factor Xa inhibitors will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3077803