Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-08
2001-03-27
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S418000, C548S409000, C548S410000, C548S486000, C548S487000
Reexamination Certificate
active
06207697
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to novel benzimidazolinones, benzoxazolinones, benzopiperazinones, indanones, and derivatives thereof as inhibitors of 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.
EP 0,540,051 and JP 06227971 describe a series of compounds useful as factor Xa inhibitors or to treat influenza based on the formula:
wherein A is an alkylene linker optionally substituted X is a bond, O, S, or carbonyl, n is 0-4, and Y is an optionally substituted carbocycle or heterocycle. The core ring containing Z can be a variety of benzofused heterocycles. However, the present invention does not involve compounds containing these benzofused heterocycles-
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT
1
agonists which are indole substituted five-membered heteroaromatic compounds of the formula:
wherein R
1
may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not appear to describe heterocycles which are part of the present invention.
Baker et al, in WO 94/02477, discuss 5-HT
1
agonists which are imidazoles, triazoles, or tetrazoles of the formula:
wherein R
1
represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. But, the presently claimed invention doesn't relate to the heterocyclic cores of Baker et al.
EP 787,727 illustrates benzyl-thiazolidin-2,4-diones of the formula:
which are useful as hypoglycemic agents. However, these type of compounds are outside of the present Xa inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel inhibitors of factor Xa 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.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors, discovery that compounds of formula (I):
or pharmaceutically acceptable salt forms thereof, wherein W, W
1
, W
2
, W
3
, J, J
a
, and J
b
are defined below, 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 I:
or stereoisomer or pharmaceutically acceptable salt thereof, wherein;
one of W, W
1
, W
2
, and W
3
is C—D and the remaining are C—R
1
;
alternatively, W-W
1
, W
1
-W
2
, or W
2
-W
3
combine to form C(D
a
)N and the remaining are C—R
1
;
D is selected from CN, C(═NR
7
)NR
8
R
9
, NHC(═NR
7
)NR
8
R
9
, NR
8
CH(═NR
7
), C(O)NR
8
R
9
, and (CH
2
)
t
NR
8
R
9
;
D
a
is NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
2
, or C
1-3
alkoxy;
J is selected from N(Z—A—B) and CR(Z—A—B); and
J
a
and J
b
together are selected from CONHCR
e
R
f
, SO
2
NHCR
e
R
f
, (CR
a
R
b
)
q
SO
2
NR
d
, and (CR
a
R
b
)
b
COCO(CR
e
R
f
)
c
, wherein b+c=0 or 1;
alternatively, J and J
a
together are selected from CON(Z—A—B) (CR
c
R
b
)
q
and N(Z—A—B)Q(R
c
R
b
)
a
; and
J
b
is selected from NR
d
, O, and CR
e
R
f
;
Q is CO or CS;
alternatively, J, J
a
and J
b
together are selected from CR(Z—A—B) (CR
a
R
b
)
a
QNR
d
, CR(Z—A—B) (CR
a
R
b
)
d
C(O)O, CR(Z—A—B) NHCOCR
e
R
f
, CR(Z—A—B)NHSO
2
CR
e
R
f
, N(Z—A—B)(CR
a
R
b
)
a
QNR
d
, N(Z—A—B)(CR
a
R
b
) C(O)O, N(Z—A—B) SO
2
(CR
c
R
b
)
a
CR
e
R
f
, N(Z—A—B) SO
2
(CR
c
R
b
)
a
NR
d
, CON(Z—A—B)CR
e
R
f
, CONR
b
(CR
c
R
b
)
a
N(Z—A—B),
R is selected from H, C
1-6
alkyl, NH
2
, NH(C
1-6
alkyl), N(C
1-6
alkyl)
2
, OH, C
1-6
alkoxy, C
1-6
alkoxy-C
1-4
alkyl, (CH
2
)
t
NR
8
R
9
, 5-6 membered aromatic heterocyclyl-C
1-4
alkyl, and aryl-C
1-4
alkyl, wherein the aromatic heterocyclyl and aryl groups are substituted with 0-1 R
4
;
R
a
is selected from H, C
1-6
alkyl, C(O)R
2b
, 5-6 membered aromatic heterocyclyl-C
1-4
alkyl, and aryl-C
1-4
alkyl, wherein the aromatic hetercyclyl and aryl groups are substituted with 0-1 R
4
;
R
b
is H or C
1-2
alkyl;
R
c
is selected from H, C
1-6
alkyl, C(O)R
2b
, S(O)
p
R
2b
, BO
2
H
2
, 5-6 membered aromatic heterocyclyl-C
1-4
alkyl, and aryl-C
1-4
alkyl, wherein the aromatic hetercyclyl and aryl groups are substituted with 0-1 R
4
;
R
d
is selected from H, OH, NH
2
, C
1-2
alkyl, and C
1-2
alkyl-OH,
alternatively, R
c
and R
d
, when attached to adjacent atoms, together form a double bond;
R
e
is selected from H, OH, NH
2
, C
1-2
alkyl, and C
1-2
alkyl-OH,
alternatively, R
c
and R
e
, when attached to adjacent atoms, together form a double bond;
R
f
is H or C
1-2
alkyl;
Z is selected from a bond, C
1-4
alkylene, (CH
2
)
r
O(CH
2
)
r
, (CH
2
)
r
NR
3
(CH
2
)
r
, (CH
2
)
r
C(O)(CH
2
)
r
, (CH
2
)
r
C(O)(CH
2
)
r
, (CH
2
)
r
OC(O)(CH
2
)
r
, (CH
2
)
r
C(O)NR
3
(CH
2
)
r
, (CH
2
)
r
NR
3
C(O)(CH
2
)
r
, (CH
2
)
r
OC(O)O(CH
2
)
r
, (CH
2
)
r
OC(O) NR
3
(CH
2
)
r
, (CH
2
)
r
NR
3
C(O) O(CH
2
)
r
, (CH
2
)
r
NR
3
C(O)NR
3
(CH
2
)
r
, (CH
2
)
r
S(O)
p
(CH
2
)
r
, (CH
2
)
r
SO
2
NR
3
(CH
2
)
r
, (CH
2
)
r
NR
3
SO
2
(CH
2
)
r
, and (CH
2
)
r
NR
3
SO
2
NR
3
(CH
2
)
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 it is attached;
R
1
, at each occurrence, is selected from H, F, Cl, Br, I, (CF
2
)
r
CF
3
, OR
2
, NR
2
R
2a
, C(O)R
2b
, (CF
2
)
r
CO
2
R
2
, S(O)
2
R
2b
, NR
2
C(O)R
2b
, C(O)NR
2
R
2a
, SO
2
NR
2
R
2a
, 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 and substituted with 0-2 R
4
;
R
1
′, at each occurrence, is selected from H, C
1-3
alkyl, F, Cl, Br, I, —CN, —CHO, (CF
2
)
r
CF
3
, (CH
2
)
r
OR
2
C NR
2
R
2a
, C(O)R
2c
, OC(O)R
2
, (CF
2
)
r
CO
2
R
2
C, S(O)
p
R
2b
, NR
2
(CH
2
)
r
OR
2
, CH(═NR
2
C)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
4b
, 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
4b
;
R
1
″, at each occurrence, is selected from
Amparo Eugene C.
Dominguez Celia
Han Qi
Park Jeongsook M.
Quan Mimi L.
DuPont Pharmaceuticals Company
Rao Deepak R.
Shah Mukund J.
Vance David H.
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