Nitrogen containing heterobicycles as factor Xa inhibitors

Details Nitrogen containing heterobicycles as factor Xa inhibitors Nitrogen containing heterobicycles as factor Xa inhibitors

1999-12-22

2002-07-02

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...

C546S117000, C546S120000, C514S303000

Reexamination Certificate

active

06413980

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to nitrogen containing heterobicycles, 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
WO94/20460 describes angiotensin II compounds of the following formula:
wherein X can be a number of substituents and Het can be a nitrogen-containing heterobicycle. However, WO94/20460 does not suggest Factor Xa inhibition or exemplify compounds like those of the present invention.
WO96/12720 describes phosphodiesterase type IV and TNF production inhibitors of the following formula:
wherein X can be oxygen and R
2
and R
3
can a number of substituents including heterocycle, heterocycloalkyl, and phenyl. However, the presently claimed compounds do not correspond to the compounds of WO96/12720. Furthermore, WO96/12720 does not suggest Factor Xa inhibition.
WO98/52948 describes inhibitors of ceramide-mediated signal transduction. One of the types of inhibitors described is of the following formula:
wherein Y
1
can be N—R
6
, R
6
can be unsubstituted aryl-alkyl or unsubstituted heterocyclic-alkyl and R
1
can be a substituted aryl group. WO98/52948 does not mention factor Xa inhibition or show compounds like those of the present invention.
U.S. Pat. Nos. 3,365,459 and 3,340,269 illustrates anti-inflammatory inhibitors of the following formula:
wherein A is 2-3 carbon atoms, X can be O, and R
1
and R
3
can be substituted or unsubstituted aromatic groups. Neither of these patents, however, exemplify compounds of the present 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 nitrogen containing heterobicycles 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 bicyclic compounds for use in therapy.
It is another object of the present invention to provide the use of novel bicyclic 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 bicyclic compounds, 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 selected from the group:
or a stereoisomer or pharmaceutically acceptable salt thereof wherein compounds of the above formulas are substituted with 0-2 R
3
;
G is a group of formula I or II:
 ring D is selected from —(CH
2
)
3
—, —(CH
2
)
4
—, —CH
2
N═CH—, —CH
2
CH
2
N═CH—, and a 5-6 membered aromatic system containing from 0-2 heteroatoms selected from the group N, O, and S, provided that from 0-1 O and S atoms are present;
ring D, when present, is substituted with 0-2 R;
E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, substituted with 0-1 R;
R is selected from Cl, F, Br, I, OH, C
1-3
alkoxy, NH
2
, NH(C
1-3
alkyl), N(C
1-3
alkyl)
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), and CH
2
CH
2
N(C
1-3
alkyl)
2
;
alternatively, ring D is absent;
when ring D is absent, ring E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, and ring E is substituted with R″ and R′;
R″ is selected from F, Cl, Br, I, OH, C
1-3
alkoxy, CN, C(═NR
8
)NR
7
R
9
, NHC(═NR
8
)NR
7
R
9
, NR
8
CH(═NR
7
), C(O)NR
7
R
8
, (CR
8
R
9
)
t
NR
7
R
8
, SH, C
1-3
alkyl-S, S(O)R
3b
, S(O)
2
R
3a
, S(O)
2
NR
2
R
2a
, and OCF
3
;
R′ is selected from H, F, Cl, Br, I, SR
3
, CO
2
R
3
, NO
2
, (CH
2
)
t
OR
3
, C
1-4
alkyl, OCF
3
, CF
3
, C(O)NR
7
R
8
, and (CR
8
R
9
)
t
NR
7
R
8
;
alternatively, R″ and R′ combine to form methylenedioxy or ethylenedioxy;
Z is N or CR
1a
;
Z
1
is S, O, or NR
3
;
Z
2
is selected from H, C
1-4
alkyl, phenyl, benzyl, C(O)R
3
, and S(O)
p
R
3c
;
R
1a
is selected from H, —(CH
2
)
r
—R
1′
, —CH═CH—R
1′
, NCH
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, Br, 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
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)R
3
, 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
4a
, 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
4a
;
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
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
, a C
3-6
carbocyclic-CH
2
- 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
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
4
b, and 5-6 membered heterocyclic system containing from 1-4 heteroato

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