Heteroaryl-phenyl substituted factor Xa inhibitors

Details Heteroaryl-phenyl substituted factor Xa inhibitors Heteroaryl-phenyl substituted factor Xa inhibitors

2001-06-22

2003-07-29

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S396000, C514S364000, C514S370000, C514S373000, C514S300000, C514S320000, C514S335000, C514S263100, C548S356100, C548S364100, C548S370100, C548S373100, C548S300100, C548S320100, C548S335100, C548S263600

Reexamination Certificate

active

06599926

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to heteroaryl-phenyl substituted compounds and derivatives thereof, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, 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 are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel heteroaryl-phenyl substituted compounds and derivatives thereof that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs 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 heteroaryl-phenyl substituted compounds for use in therapy.
It is another object of the present invention to provide the use of novel heteroaryl-phenyl substituted compounds for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed heteroaryl-phenyl substituted compounds and derivatives thereof, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula Ia, Ib, or Ic:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;
ring D
1
is selected from pyridine, pyrazine, pyridazine, and pyrimidine and is substituted with 1 R
a
and 0-1 R
b
;
ring D
2
is a 5-membered heteroaromatic ring system comprising E, carbon atoms, and 0-3 N atoms, wherein E is selected from O, S, and N-R
c
and ring D
2
is substituted with 1 R
a
and 0-1 R
b
;
ring D
3
is a 5-membered heteroaromatic ring system comprising carbon atoms and from 0-3 additional N atoms and ring D
3
is substituted with 1 R
a
and 0-1 R
b
;
R is selected from H, C
1-4
alkyl, F, Cl, Br, I, OH, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, OCH
2
CH
2
CH
3
, CN, C(═NR
8
)NR
7
R
9
, NHC(═NR
8
)NR
7
R
9
, NR
8
CH(═NR
7
), NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, C(═NH)NH
2
, CH
2
NH
2
, CH
2
NH(C
1-3
alkyl), CH
2
N(C
1-3
alkyl)
2
, CH
2
CH
2
NH
2
, CH
2
CH
2
NH(C
1-3
alkyl), CH
2
CH
2
N(C
1-3
alkyl)
2
, (CR
8
R
9
)
t
NR
7
R
8
, (CR
8
R
9
)
t
C(O)NR
7
R
8
, and OCF
3
;
R
a
is selected from H, C
1-4
alkyl, F, Cl, Br, I, OH, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, OCH
2
CH
2
CH
3
, CN, C(═NR
8
)NR
7
R
9
, NHC(═NR
8
)NR
7
R
9
, NR
8
CH(═NR
7
), NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, C(═NH)NH
2
, CH
2
NH
2
, CH
2
NH(C
1-3
alkyl), CH
2
N(C
1-3
alkyl)
2
, CH
2
CH
2
NH
2
, CH
2
CH
2
NH(C
1-3
alkyl), CH
2
CH
2
N(C
1-3
alkyl)
2
, (CR
8
R
9
)
t
NR
7
R
8
, (CR
8
R
9
)
t
C(O)NR
7
R
8
, and OCF
3
;
R
b
is selected from H, (C
1-4
alkyl, F, Cl, Br, I, OH, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, OCH
2
CH
2
CH
3
, CN, C(═NR
8
)NR
7
R
9
, NHC (═NR
8
)NR
7
R
9
, NR
8
CH(═NR
7
), NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, C (═NH)NH
2
, CH
2
NH
2
, CH
2
NH(C
1-3
alkyl), CH
2
N(C
1-3
alkyl)
2
, CH
2
CH
2
NH
2
, CH
2
CH
2
NH(C
1-3
alkyl), CH
2
CH
2
N(C
1-3
alkyl)
2
, (CR
8
R
9
)
t
NR
7
R
8
, (CR
8
R
9
)
t
C(O)NR
7
R
8
, and OCF
3
;
R
c
is selected from H, C
1-4
alkyl, OCH
3
, OCH
2
CH
3
, OCH(CH
3
)
2
, OCH
2
CH
2
CH
3
, NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, C(═NH)NH
2
, CH
2
NH
2
, CH
2
NH(C
1-3
alkyl), CH
2
N(C
1-3
alkyl)
2
, CH
2
CH
2
NH
2
, CH
2
CH
2
NH(C
1-3
alkyl), CH
2
CH
2
N(C
1-3
alkyl)
2
, (CR
8
R
9
)
t
NR
7
R
8
, (CR
8
R
9
)
t
C(O)NR
7
R
8
, and OCF
3
;
G is absent or is selected from CH
2
, C(O), O, NR
3
, S(O)
p
, CH
2
CH
2
, C(O)CH
2
, CH
2
C(O), OCH
2
, CH
2
O, NR
3
CH
2
, CH
2
NR
3
, S(O)
p
CH
2
, CH
2
S(O)
p
, CH
2
CH
2
CH
2
, C(O)CH
2
CH
2
, CH
2
C(O)CH
2
, CH
2
CH
2
C(O), OCH
2
CH
2
, CH
2
OCH
2
, CH
2
CH
2
O, NR
3
CH
2
CH
2
, CH
2
NR
3
CH
2
, CH
2
CH
2
NR
3
, S(O)
p
CH
2
CH
2
, CH
2
S(O)
p
CH
2
, and CH
2
CH
2
S(O)
p
;
G
1
is absent or is selected from (CR
3
R
3a
)
1-5
, (CR
3
R
3a
)
0-2
CR
3
═CR
3
(CR
3
R
3a
)
0-2
(CR
3
R
3a
)
0-2
C≡C (CR
3
R
3a
)
0-2
, (CR
3
R
3a
)
u
C(O) (CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
C(O)O(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
OC(O) (CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
O(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
NR
3
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
C(O)NR
3
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
NR
3
C(O) (CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
OC(O)NR
3
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
NR
3
C(O)O(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
NR
3
C(O)NR
3
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
NR
3
C(S)NR
3
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
S (CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
S(O) (CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
S(O)
2
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
S(O)NR
3
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
NR
3
S(O)
2
(CR
3
R
3a
)
w
, (CR
3
R
3a
)
u
S(O)
2
NR
3
(CR
3
R
3a
)
w
, and (CR
3
R
3a
)NR
3
S(O)
2
NR
3
(CR
3
R
3a
)
w
, wherein u+w total 0, 1, 2, 3, or 4, provided that G
1
does not form a N—N, N—O, N—S, NCH
2
N, NCH
2
O, or NCH
2
S bond with either group to which it is attached;
G
2
is phenyl, naphthyl, or a 5-10 membered heteroaryl consisting of carbon atoms and from 1-3 heteroatoms selected from N, O, and S;
M is isoxazoline, pyrazoline, isothiazoline, triazoline, tetrazoline, phenyl, or a 5-6 membered aromatic heterocycle consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S, and is substituted with -Z-A-B;
M is also substituted with 0-2 R
1a
;
Z is selected from a bond, —(CR
2
R
2a
)
1-4
—, (CR
2
R
2a
)
q
O(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
NR
3
(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
C(O) (CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
C(O)O(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
OC(O) (CR
2
R
2a
)
q
1
(CR
2
R
2a
)
q
C(O)NR
3
(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
NR
3
C(O) (CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
OC(O)O(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
OC(O)NR
3
(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
NR
3
C(O)O(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
1
NR
3
C(O) NR
3
(CR
2a
)
q
1
, (CR
2
R
2a
)
q
S(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
S(O) (CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
S(O)
2
(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
SO
2
NR
3
(CR
2
R
2a
)
q
1
, (CR
2
R
2a
)
q
NR
3
SO
2
(CR
2
R
2a
)
q
1
, and (CR
2
R
2a
)
q
NR
3
SO
2
NR
3
(CR
2
R
2a
)
q
1
, wherein q+q
1
total 0, 1, or 2, provided that Z d

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